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Original article
BDNF Val66Met polymorphism is associated with negative symptoms in early-onset schizophrenia spectrum and other psychotic disorders
G. Karacetina,
Corresponding author
drgul21@yahoo.com

Corresponding author at: University of Health Sciences, Bakirkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Clinic of Child and Adolescent Psychiatry, Zuhuratbaba, Doktor Tevfik Sağlam Street 25/2, 34147 Bakirkoy/Istanbul, Turkey.
, B. Bayoglub, T. Eseroglu Soylemezc, M. Topald, E. Bulanik Koca, M. Tekdena, C. Ermise, T. Demirf, M. Elagoz Yukselg, E.S. Ercanh, M. Erkirani, S.B. Aksoyer Sezginj, M. Cengizb
a University of Health Sciences, Bakirkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Clinic of Child and Adolescent Psychiatry, Istanbul, Turkey
b Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Department of Medical Biology, Istanbul, Turkey
c Başkent University İstanbul Medical Research and Practice Center, Department of Child and Adolescents Psychiatry, Istanbul, Turkey
d Karabuk University, Research and Training Hospital, Clinic of Child and Adolescent Psychiatry, Istanbul, Turkey
e Dokuz Eylül University, Medical Faculty, Department of Child and Adolescent Psychiatry, Izmir, Turkey
f Specialist of Child and Adolescent Psychiatrist, Istanbul, Turkey
g Uskudar University Medical Faculty, Department of Psychiatry, Istanbul, Turkey
h Ege University, Medical Faculty, Department of Child and Adolescent Psychiatry, Izmir, Turkey
i University of Health Sciences, Bakirkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Clinic of Psychiatry, Turkey
j Biruni University, Vocational School Dialysis Programme, Istanbul, Turkey
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Schizophrenia spectrum and other psychotic disorders &#40;SSD&#41; have been considered as multifactorial neurodevelopmental disorders arisen from the complex interactions of many genes and environmental conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Studies reported the heritability estimates of schizophrenia could be approximately between 80&#8211;85&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Family&#44; twin&#44; and adoption studies across all age groups have revealed the polygenic model based on the interplay of multiple genes could be more likely to fit schizophrenia&#44; rather than the effect of a single gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> Early-onset schizophrenia &#40;EOS&#41; had several genetic components demonstrated in the previous literature&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Investigating schizophrenia susceptibility genes composing the genetic components of EOS is also crucial for clarifying the underlying etiology of the disease&#46; Studies to date have shown EOS might be associated with a wide variety of copy number variations and single nucleotide variations&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Brain-derived neurotrophic factor &#40;BDNF&#41; is a member of the neurotrophin family that plays an important role in the development&#44; differentiation&#44; neuroplasticity&#44; and synaptogenesis of neurons&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#8211;7</span></a> According to the neurodevelopmental hypothesis of schizophrenia&#44; impairments in synaptogenesis and neuroplasticity could give rise to structural abnormalities in certain areas of the brain associated with the etiology of illness&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Therefore&#44; many studies evaluating the symptomatology of schizophrenia focused on serum BDNF levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;14</span></a> The substitution of valine to methionine in the codon 66 of the precursor BDNF &#40;proBDNF&#41; protein&#44; called Val66Met polymorphism&#44; results in the disruption of activity-dependent BDNF release&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;15</span></a> Current evidence revealed no clear relationship between the Val66Met polymorphism of the BDNF gene and the development of schizophrenia&#46; However&#44; Val66Met was found to be associated with various clinical features of schizophrenia including the age of onset&#44; treatment response&#44; and cognitive dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;16&#8211;25</span></a> Some evidence indicated Val66Met was also associated with earlier age-onset and paranoid symptoms among adult patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;29</span></a> Although many studies have been performed in adult patients&#44; relatively few studies have been implemented to investigate Val66Met polymorphism among subjects with SSD or EOS&#44; revealing inconclusive findings for clinical characteristics&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;28&#44;30</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A significant body of research has been conducted to investigate the relationship between the dopamine D2 receptor gene &#40;DRD2&#41; and treatment response&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;32</span></a> DRD2 located in the 11q22-q23 region exhibits clinically relevant polymorphisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#8211;33</span></a> Of these&#44; The Taq1A polymorphism &#40;known as rs1800497&#44; C&#47;T&#44; Glu713Lys&#41; was previously thought to be located in DRD2&#44; then it was identified within exon 8 of the ankyrin repeat and kinase domain-containing 1 &#40;ANKK1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> In the previous studies&#44; compared to the A2 allele&#44; the presence of the A1 allele could affect DRD2 gene expression&#44; which could be associated with lower D2 receptor density in the striatum&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> Taq1A has become a research interest for both psychosis and alcohol&#47;substance use disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#8211;42</span></a> Several studies also have shown that the Taq1A polymorphism of DRD2&#47;ANKK1 increases susceptibility to schizophrenia&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44</span></a> Nevertheless&#44; meta-analyses did not find any clear effect of Taq1A polymorphism on the risk of schizophrenia and treatment outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;41&#44;45&#44;46</span></a> However&#44; in the existing literature&#44; early-onset psychosis was not extensively investigated for the clinical implications of DRD2&#47;ANNK1 variants&#46; In one study&#44; neurocognitive features of the patients aged between 7&#8211;17 years with the first episode psychosis were not found to be associated with DRD2 TaqA1 variants&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Yet&#44; this study endorsed both non-affective and affective psychosis&#44; and its results were mainly limited to neuropsychological assessments&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Therefore&#44; compared to adult-onset schizophrenia&#44; more studies are still needed to fill the gap in the field of EOS and SSD&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Given the underlying genetic etiology of SSD in the child and adolescent population was not clearly understood&#44; there is still a paucity of knowledge about the clinical characteristics of EOS and SSD in terms of the above-mentioned genetic alterations&#46; The importance of Val66Met and&#47;or DRD2 Taq1A polymorphisms was previously shown for the age-onset&#44; clinical characteristics&#44; treatment response&#44; and clinical symptoms of schizophrenia&#46; In this study&#44; we focused on the Val66Met and DRD2 Taq1A polymorphisms in adolescents with early-onset full psychotic disorders&#46; To this end&#44; we aimed to demonstrate the clinical features of cases with an early-onset SSD regarding Val66Met or Taq1A polymorphisms&#46; Also&#44; we compared the prevalence of BDNF Val66Met and DRD2&#47;ANKK1 Taq1A gene polymorphisms among patients with SSD and healthy controls&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Participants and clinical procedures</span><p id="par0025" class="elsevierStylePara elsevierViewall">251 subjects involving 101 cases with SSD and 150 healthy controls participated in the study&#46; Patients with SSD were recruited from the inpatient units of a tertiary care psychiatry-teaching mental health hospital&#46; A disease-free control group was taken from the outpatient clinics of the child health and disease department&#46; Healthy controls were only allowed when they did not have any chronic medical illness&#46; Healthy controls also matched with the SSD group regarding their demographic characteristics&#46; All the participants&#44; both patients&#44; and caregivers gave written informed consent before the inclusion&#46; The Local Ethics Committee of Cerrahpasa University Medical Faculty approved the study&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">All psychiatric interviews were conducted by experienced clinicians specialized in child and adolescent psychiatry&#46; Research diagnoses of psychotic disorders were determined as per the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV-Text Revision &#40;DSM-IV-TR&#41;&#46; According to the definition&#44; a non-affective early-onset psychotic disorder was endorsed when patients were fully syndromal under the age of 18&#46; Our exclusion criteria were i&#41; caregivers who were not able to give reliable information during the diagnostic interview due to intellectual disability and ii&#41; chronic medical illnesses that might affect mental health&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The positive and Negative Symptom Scale &#40;PANSS&#41; was implemented to assess the severity of the psychotic symptoms&#46; PANSS was developed for the categorical and dimensional evaluation of schizophrenia&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Kostakoglu et al&#46; demonstrated the reliability and validity of the scale in the Turkish population&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Likert-type 7-point severity scale was used for positive symptoms &#40;7 items&#41;&#44; negative symptoms &#40;7 items&#41;&#44; and general psychopathology symptoms &#40;16 items&#41;&#46; All items of these three subscales were rated by an experienced clinician in the child and adolescent psychiatry field&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Genotyping procedures</span><p id="par0040" class="elsevierStylePara elsevierViewall">Venous blood samples were drawn from both study groups using EDTA tubes&#46; Genomic DNA was purified from peripheral blood using a commercial kit &#40;Roche Diagnostics&#44; Mannheim&#44; Germany&#41;&#46; The DRD2 Taq1A &#40;rs1800497&#41; and BDNF Val66Met &#40;rs6265&#41; single nucleotide polymorphisms &#40;SNPs&#41; genotyping have been performed in the real-time polymerase chain reaction &#40;RT-PCR&#41; method&#46; Hybridization probes were used for SNP genotyping &#40;TIB MOLBIOL&#44; GmbH&#44; Berlin&#44; Germany&#41;&#46; Light-Cycler 1&#46;5&#174; system was used to detect the variants&#46; Genotyping was achieved in a total of 20&#8239;mL volume having 2&#46;0&#8239;mL of Master Mix&#44; 1&#46;0&#8239;mL reagent mix&#44; 3&#46;0&#8239;mM MgCl2 &#40;Roche Diagnostics&#44; Mannheim&#44; Germany&#41;&#44; and 50&#8239;ng of genomic DNA&#46; The genotyping quality was validated by amplifying the randomly selected samples&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Statistical analyses</span><p id="par0045" class="elsevierStylePara elsevierViewall">The Student&#39;s <span class="elsevierStyleItalic">t</span>-test or Mann-Whitney <span class="elsevierStyleItalic">U</span> test was used as per the normality of distribution to compare continuous variables&#46; The chi-square test or Fisher&#39;s exact test was preferred for the categorical variables&#46; Genotype&#47;allelic relations among study participants were tested using Hardy-Weinberg equilibrium &#40;HWE&#41; and the chi-square test&#46; Since very few patients with Met&#47;Met genotype of BDNF and Lys&#47;Lys genotype of DRD2&#47;ANNK1 variants were available&#44; we opted to exclude these allelic variants from subgroup comparisons to reduce heterogeneity&#46; The effect size of the significant results was also calculated &#40;Cohen&#8217;s d&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Logistic regression analysis was performed to determine the odds ratio of categorical variables that differed between study subgroups&#46; Alpha value was set at 0&#46;05 two-sided for the lowest threshold of statistical significance&#46; False discovery rate correction was not implemented regarding the explorative and hypothesis-generating features of the study in the early-onset cases&#46; Statistical Package for Social Sciences &#40;SPSS&#41; Version 24&#46;0 was used for data analysis &#40;IBM Corp&#44; Armonk&#44; NY&#41;&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> demonstrated demographic information and allelic variants of the study participants&#46; The average age of the SSD group was comparable to that of healthy controls &#40;16&#46;3&#8239;&#177;&#8239;1&#46;3 years vs&#46; 16&#46;5&#8239;&#177;&#8239;3&#46;2 years&#44; p&#8239;&#61;&#8239;0&#46;578&#41;&#46; There was no statistically significant difference between study groups for the frequencies of male and female patients &#40;p&#8239;&#61;&#8239;0&#46;392&#41;&#46; The genotype distributions were consistent with HWE expectations for DRD2 Taq1A and BDNF Val66Met polymorphism among patients and controls &#40;all p values &#62;0&#46;05&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The genotype distribution of DRD2 Taq1A polymorphism in patient group were similar to control group &#40;For patients&#44; CC&#8239;&#61;&#8239;65&#44;3&#37;&#44; CT&#8239;&#61;&#8239;31&#44;7&#37;&#44; TT&#8239;&#61;&#8239;3&#46;0&#37;&#59; for controls CC&#8239;&#61;&#8239;74&#44;7&#37;&#44; CT&#8239;&#61;&#8239;22&#44;7&#37;&#44; TT&#8239;&#61;&#8239;2&#44;7&#37;&#44; p&#8239;&#61;&#8239;0&#46;269&#41;&#46; The genotype frequencies of BDNF Val66Met polymorphism also did not differ between study groups &#40;In patient group&#44; GG&#8239;&#61;&#8239;73&#44;3&#37;&#44; GA&#8239;&#61;&#8239;24&#44;8&#37;&#44; AA&#8239;&#61;&#8239;2&#46;0&#37;&#59; in control group GG&#8239;&#61;&#8239;70&#46;0&#37;&#44; GA&#8239;&#61;&#8239;28&#46;0&#37; and AA&#8239;&#61;&#8239;2&#46;0&#37;&#44; p&#8239;&#61;&#8239;0&#46;848&#41;&#46; There was no significant difference regarding the frequencies of DRD2 Taq1A and BDNF Val66Met alleles in study groups &#40;p&#8239;&#62;&#8239;0&#46;05 for both&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> demonstrates patient subgroups either with homozygote &#40;Glu&#47;Glu&#41; or heterozygote &#40;Glu&#47;Lys&#41; DRD2&#47;ANKK1 Taq1A allelic variants&#46; SSD patients having Glu&#47;Glu allele had similar age and sex characteristics with Glu&#47;Lys group &#40;16&#46;2&#8239;&#177;&#8239;1&#46;2 years vs&#46; 16&#46;4&#8239;&#177;&#8239;1&#46;4 years&#44; p&#8239;&#61;&#8239;0&#46;445&#59; &#37;36&#46;4 female vs&#46; &#37;28&#46;1 female&#44; p&#8239;&#61;&#8239;0&#46;418&#44; consecutively&#41;&#46; On the other hand&#44; SSD patients who carried Lys&#47;Glu polymorphism had higher levels of substance use than Glu&#47;Glu carriers &#40;40&#46;6&#37; vs&#46; 15&#46;2&#37;&#44; p&#8239;&#61;&#8239;0&#46;005&#41;&#46; Total PANSS scores of positive symptoms&#44; negative symptoms&#44; and general psychopathology items did not differ for both study groups&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">SSD patients were also divided into Val&#47;Val and Val&#47;Met groups for BDNF Val66Met polymorphism&#46; Both study groups had similar sociodemographic characteristics regarding age&#44; sex&#44; the duration of untreated illness&#44; and family history of psychiatric disorders &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Besides&#44; the age-onset of psychotic disorders did not reveal any statistical difference Val66Met variants &#40;Val&#47;Val group&#8239;&#61;&#8239;15&#46;1&#8239;&#177;&#8239;1&#46;8 years vs&#46; Val&#47;Met group&#8239;&#61;&#8239;15&#46;5&#8239;&#177;&#8239;1&#46;2 years&#44; p&#8239;&#61;&#8239;0&#46;573&#41;&#46; Additionally&#44; after excluding female patients with SSD&#44; the age-onset of male patients was not also statistically different between both genotypes &#40;Val&#47;Val group&#8239;&#61;&#8239;15&#46;3&#8239;&#177;&#8239;1&#46;9 vs&#46; Val&#47;Met group&#8239;&#61;&#8239;15&#46;6&#8239;&#177;&#8239;0&#46;9&#44; p&#8239;&#61;&#8239;0&#46;976&#41;&#46; Val&#47;Val group had a higher score of negative symptoms in PANSS compared to Val&#47;Met group &#40;28&#46;6&#8239;&#177;&#8239;8&#46;5 vs&#46; 24&#46;6&#8239;&#177;&#8239;5&#46;8&#44; p&#8239;&#61;&#8239;0&#46;018&#44; Cohen&#8217;s d&#8239;&#61;&#8239;0&#46;55&#41;&#46; We divided SSD patients into two equal subgroups from the median value of negative symptoms&#46; This analysis also indicated the prevalence of Val&#47;Val and Val&#47;Met genotypes in both negative symptom groups were significantly different &#40;&#967; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">2</span></span>&#8239;&#61;&#8239;4&#46;2&#44; p&#8239;&#61;&#8239;0&#46;040&#41;&#46; The positive symptom subscale of PANSS did not differ between Val&#47;Val and Val&#47;Met groups &#40;27&#46;0&#8239;&#177;&#8239;7&#46;5 vs&#46; 27&#46;9&#8239;&#177;&#8239;8&#46;0&#44; p&#8239;&#61;&#8239;0&#46;882&#41;&#46; Finally&#44; general psychopathology and total PANSS score were similar between BDNF Val66Met variants&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">We implemented a logistic regression analysis for the presence of substance use to calculate odd ratios of Val&#47;Met and Glu&#47;Lys variants &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; DRD2&#47;ANNK1 Taq1A polymorphism remained significant in the model &#40;Wald&#8239;&#61;&#8239;7&#46;2&#44; p&#8239;&#61;&#8239;0&#46;007&#41;&#46; Exp&#40;B&#41; value of the Glu&#47;Lys allele was 4&#46;9 &#40;95&#37;CI&#8239;&#61;&#8239;1&#46;5&#8211;15&#46;6&#41; comparing to Glu&#47;Glu allele&#46; BDNF Val66Met polymorphism and BDNF&#42;DRD2&#47;ANKK1 interaction was not statistically significant in the logistic regression model&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Our study contributed to the extant knowledge by demonstrating the link between clinical features and genotype within an EOS&#47;SSD sample&#46; Considering multiple genes and environment play a key role in the development of psychosis&#44; genotype-related illness characteristics have become more important to understand the etiology of psychotic disorders in youth&#46; Specifically&#44; higher negative symptom levels and the presence of substance use were crucial clinical aspects of the illness that were associated with the genotype of patients&#46; Accordingly&#44; the results of this study suggested a higher prevalence of substance use in the DRD2&#47;ANKK1 A1A2 &#40;Glu&#47;Lys&#41; allele compared to the A2A2 &#40;Glu&#47;Glu&#41; counterparts&#46; Val&#47;Met heterozygotes had decreased levels of negative symptoms in comparison to Val&#47;Val homozygotes&#46; Other clinical characteristics between patient subgroups did not differ regarding age-onset&#44; clinical symptomatology&#44; family history&#44; and substance use&#46; Both healthy controls and patients with EOS&#47;SSD did not have any deviation from HWE&#46; Genotype frequencies of study groups were not distinctive&#44; indicating a lack of association for both genes in psychotic spectrum disorders&#46; Finally&#44; logistic regression analysis did not show any additive effect of Val66Met polymorphism on substance use&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In line with the previous literature&#44; DRD2 Taq1A polymorphism was found to be associated with substance use in our study population&#46; As previously stated&#44; current evidence did not support the notion that DRD2 Taq1A modifies the risk of schizophrenia and the clinical aspects of the illness&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;41&#44;45&#44;46</span></a> A study by Aslan et al&#46; also did not find any association between DRD2 rs1800497 polymorphism and schizophrenia&#44; providing further evidence for the Turkish population&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Also&#44; there was no significant effect of DRD2 Taq1A polymorphism on the neurocognitive features of EOS patients&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> In other respects&#44; current knowledge indicated a relationship between the DRD2&#47;ANKK1 Taq1A polymorphism and alcohol use disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Previous research also suggested DRD2 Taq1A A1&#47;A1 genotype carriers were more prone to cannabis use&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;53</span></a> Cannabis use was known to play a putative role in psychosis development in vulnerable populations&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> More specifically&#44; Kraan et al&#46; &#40;2016&#41; demonstrated that current cannabis use had a significant impact on psychosis development in ultra-high risk populations rather than lifetime cannabis use&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> A recent meta-analysis suggested that nearly a quarter of patients with SSD reported cannabis use&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> The presence of any substance use disorder was also estimated as 41&#46;7&#37; within the SSD population&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> In a study conducted in the first-episode psychosis population&#44; Colizzi et al&#46; &#40;2015&#41; showed patients carrying T allele of rs1076560 polymorphism in DRD2 gene more commonly reported cannabis use than controls&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> Another study including cannabis users suggested higher levels of hypermethylation at exon 8 of DRD2&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> When taken together&#44; DRD2&#47;ANKK1 Taq1A polymorphism was associated with substance use but not with the risk of psychosis&#44; this polymorphism could alter the course of illness&#46; In parallel with these results&#44; our findings suggested DRD2&#47;ANKK1 Taq1A polymorphism was not associated with the risk of EOS&#47;SSD&#46; Yet&#44; it could be a risk factor for substance use among patients with early-onset psychosis&#44; which indirectly affects the prognosis of the illness&#46; Increased prevalence of substance use in DRD2 Taq1A Glu&#47;Lys genotype might point to an interaction between DRD2 gene alterations and substance use&#46; Some patients might be inherently more susceptible to substance use that might complicate the course of illness&#46; Nevertheless&#44; our cross-sectional study similar to the previous research was not able to clarify this hypothesis for the longitudinal course&#46; Considering the increasing body of literature emphasizing the impact of cannabis use on psychosis development&#44; clinical and community-based cohorts should explicate this finding&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Consistent with the previous literature&#44; our results proposed the lack of association between BDNF Val66Met polymorphism and EOS&#47;SSD&#46; In a study with adult subjects&#44; Chang et al&#46; &#40;2009&#41; categorized patients with schizophrenia regarding the presence of positive family history or an early-onset illness&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Their findings did not support an association between BDNF Val66Met polymorphism and EOS&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Similarly&#44; they found higher levels of negative symptoms among Val&#47;Val genotype compared to Met carriers&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Conversely&#44; Sun et al&#46; found a higher level of negative symptoms in Met carriers&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Nevertheless&#44; some investigators found similar levels of negative symptoms among the three genotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Another study with adult patients with schizophrenia suggested serum BDNF levels were positively correlated with emotional and social withdrawal symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Akyol et al&#46; &#40;2015&#41; also compared patients having deficit syndrome &#40;DS&#41; with the non-deficit &#40;ND&#41; group and healthy controls in terms of serum BDNF levels&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> Their results proposed lower serum BDNF levels in DS than the ND counterparts&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> ND group also had similar serum BDNF levels to those of healthy controls in this study&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> In contrast&#44; Valiente-Gomez et al&#46; &#40;2014&#41; found comparable BDNF levels between DS and ND subgroups&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Although previous results were not consistent for the difference in negative symptoms levels&#44; our results indicated higher negative symptom severity for Val&#47;Val genotype&#46; This is especially important when considering negative symptoms were clinically predominant in early-onset cases&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> Furthermore&#44; severe negative symptoms pose a further risk for treatment failure on the long-term course of EOS&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> Therefore&#44; genotype-based differences in negative symptoms could be associated with the etiologic difference for the development of psychosis&#46; On the other hand&#44; it might be argued that different DSM diagnoses&#44; illness duration&#44; medication status&#44; and assessment tools for negative symptoms could account for the previous inconclusive results regarding the effects of BDNF polymorphisms&#46; Since our sample included various SSD diagnoses&#44; the effect of the Val66Met genotype on EOS still requires further exploration by using more comprehensive assessment tools for negative symptoms&#46; Considering that current evidence provided discrepant findings for both serum BDNF levels and BDNF gene polymorphisms&#44; reliable neural correlates of BDNF activity also could be helpful to establish its role in negative symptoms&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Somewhat surprisingly&#44; we could not find any difference in the age-onset of illness between Val&#47;Val and Val&#47;Met groups&#46; Previous literature yielded an earlier illness onset among Val&#47;Met carriers&#44;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;29</span></a> which was more prominent in male patients&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Yi et al&#46; &#40;2011&#41; also replicated this finding in the EOS population&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> They found an earlier-age onset of male patients with Met allele in Kaplan-Meier survival analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Our sample size&#44; smaller than both former studies&#44; might not provide the required power to reach statistical significance&#46; Besides&#44; SSD diagnoses have heterogeneous onset patterns including insidious and abrupt illness-onset&#46; Accordingly&#44; it could be hypothesized that the effects of Val66Met might be more prominent in schizophrenia that generally show a gradual onset pattern&#44; rather than other psychotic disorders&#46; One meta-analysis suggested BDNF Val66Met polymorphism could also be a risk factor for substance use disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> However&#44; in our study&#44; we could not confirm the effect of Val66Met polymorphism on substance use in early-onset illness&#46; According to our results&#44; DRD2&#47;ANKK1 Taq1A polymorphism had a prominent role in substance use rather than BDNF Val66Met&#46; Considering the alterations in the dopamine system are involved in the pathogenesis of psychosis&#44; BDNF polymorphisms could be associated with negative symptoms linked to the prefrontal cortex and DRD2 might have a role in the striatal reward system&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> Therefore&#44; it could be argued that BDNF and DRD2 have different etiologic roles in early-onset psychosis&#46; Besides&#44; in our sample&#44; Val&#47;Val and Val&#47;Met groups yielded similar levels of positive and general symptoms&#46; This finding was not parallel with the previous literature asserting higher levels of symptomatology in Met carriers including positive symptoms&#44; depression&#44; and anxiety&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;27&#44;29&#44;60</span></a> However&#44; we only included acutely admitted psychotic patients&#44; which also should be considered to interpret the levels of positive and general symptoms&#46; Of note&#44; the severity of positive symptoms&#44; depression&#44; and anxiety might fluctuate in the course of SSD&#44; depending on the illness severity and medications&#46; Therefore&#44; it would be more beneficial to analyze symptom levels of SSD subgroups at the remission state or in the course of chronic illness&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Our results should be taken into account with their limitations&#46; First&#44; we investigated only two different polymorphisms &#40;rs1800497 and rs6265&#41; in the early-onset SSD&#46; Yet&#44; a wide range of polymorphisms has been defined for both genes in the current knowledge&#46; Therefore&#44; the findings of this study were limited to rs1800497 and rs6265 polymorphisms rather than other possible variants of both genes&#46; These polymorphisms are generally prominent in the extant literature regarding the studies involving adult cases with schizophrenia&#46; Second&#44; the sample size of our study was modest given the newly emerging studies generally involve quite a few participants from large consortiums&#46; Third&#44; early-onset psychotic disorders are composed of heterogenous psychiatric diagnoses that might show different levels of positive&#44; negative&#44; and neurocognitive symptoms&#46; Thus&#44; affective symptoms and returning to the premorbid level of functioning after remission might depend on the DSM diagnosis&#46; Similarly&#44; the cross-sectional design of our study might impede predicting the clinical outcome for the long-term follow-up&#46; Despite all these limitations&#44; studies investigating early-onset SSD were outnumbered by those conducted in adult patients&#46; Our study contributed to the relatively limited literature on SSD&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In clinical practice&#44; most patients suffer from negative symptoms causing significant illness-related burdens&#46; Higher rates of negative symptoms in the Val&#47;Val genotype of the BDNF gene could shed light on various outcomes of illness&#46; Accordingly&#44; it could be helpful for future efforts to characterize individuals with severe negative symptoms based on different allelic variants&#46; Likewise&#44; DRD2 polymorphisms could change dopamine sensitivity and facilitate substance use in youth&#46; This variation comes to the fore to prevent a poor prognosis of patients with persistent substance use&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusion</span><p id="par0105" class="elsevierStylePara elsevierViewall">Val66Met polymorphism could be a disease-modifying marker for SSD&#46; Increased frequency of substance use in A1 allele carriers might indicate a possible interaction between genes and the environment&#46; Longitudinal studies involving the high-risk group could investigate this interaction to improve our understanding&#46; These efforts will lead to genotype-based approaches to improve the outcomes of individuals with early-onset psychosis&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Ethical considerations</span><p id="par0110" class="elsevierStylePara elsevierViewall">All the participants&#44; both patients&#44; and caregivers gave written informed consent before the inclusion and all the ethical procedures were performed&#46; The Local Ethics Committee of Cerrahpasa University Medical Faculty approved the study&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Funding</span><p id="par0115" class="elsevierStylePara elsevierViewall">This study was funded by the <span class="elsevierStyleGrantSponsor" id="gs0005">Scientific Research Projects Coordination Unit of Istanbul University-Cerrahpasa</span>&#46; Project numbers&#58; <span class="elsevierStyleGrantNumber" refid="gs0005">42496</span>&#44; <span class="elsevierStyleGrantNumber" refid="gs0005">54033</span>&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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    "fechaRecibido" => "2020-10-06"
    "fechaAceptado" => "2021-04-20"
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            1 => "BDNF Val66Met genotypes"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and Objectives</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">To investigate the clinical characteristics of adolescents with early-onset full psychotic disorders either with Brain-derived neurotrophic factor &#40;BDNF&#41; Val66Met &#40;rs6265&#41; or DRD2&#47;ANKK1 Taq1A &#40;rs1800497&#41; polymorphisms&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Method</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">101 cases with early-onset schizophrenia &#40;EOS&#41; or other psychotic spectrum disorders &#40;SSD&#41; and 150 healthy controls were included in the current study&#46; Using the Positive and Negative Symptom Scale &#40;PANSS&#41;&#44; patient subgroups were compared for their psychotic symptoms&#44; age-onset&#44; duration of untreated illness&#44; and family history of psychiatric disorders&#46; The real-time polymerase chain reaction &#40;RT-PCR&#41; was implemented for genotyping procedures&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Study groups and patient subgroups were similar regarding their sociodemographic characteristics &#40;16&#46;4&#8239;&#177;&#8239;2&#46;6 years&#44; 62&#46;2&#37; male for all participants&#41;&#46; Results did not reveal any difference between patients and healthy controls for DRD2&#47;ANKK1 Taq1A and BDNF Val66Met genotypes&#46; Patients with A1A2 &#40;Gly&#47;Lys&#41; allele reported higher rates of substance use compared to A2A2 &#40;Glu&#47;Glu&#41; counterparts&#46; Other clinical variables were found similar&#46; EOS&#47;SSD group with Val66Met heterozygote allele revealed lower levels of negative symptoms than Val&#47;Val homozygotes&#46; Conversely&#44; the age onset of full psychotic disorder&#44; total positive symptom score&#44; and total general psychopathology score of PANSS were found comparable between Val&#47;Met and Val&#47;Val groups&#46; In the logistic regression model&#44; Glu&#47;Lys genotypes remained significant for the presence of substance use&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The interaction between substance use and the DRD2 gene should be investigated for the development of early-onset psychotic disorders&#46; BDNF Val66Met polymorphism also could be a disease-modifying factor for the presence of negative symptoms&#46;</p></span>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Glu&#58; glutamate&#44; Lys&#58; lysine&#44; Met&#58; methionine&#44; SD&#58; standard deviation&#44; SSD&#58; schizophrenia spectrum&#44; and other psychotic disorders&#44; Val&#58; valine&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SSD group&#44; n&#8239;&#61;&#8239;101&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control group&#44; n&#8239;&#61;&#8239;150&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&#967; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">2</span> &#47; t</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Demographic information&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Age&#44; years&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">16&#46;3&#8239;&#177;&#8239;1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">16&#46;5&#8239;&#177;&#8239;3&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;578&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Sex&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;733&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;392&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66 &#40;65&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">90 &#40;60&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;34&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DRD2 Taq1A polymorphism&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;269&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Glu&#47;Glu&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66 &#40;65&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">112 &#40;74&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Glu&#47;Lys&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;31&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;22&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">4 &#40;2&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Allele frequency&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">164 &#40;0&#46;81&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">258 &#40;0&#46;86&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">BDNF Val66Met polymorphism&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Allele frequency&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">173 &#40;0&#46;86&#41;&nbsp;\t\t\t\t\t\t\n
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                  """
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Glu&#58; glutamate&#44; Lys&#58; lysine&#44; SD&#58; standard deviation&#44; SSD&#58; schizophrenia spectrum&#44; and other psychotic disorders&#46;</p><p id="spar0021" class="elsevierStyleSimplePara elsevierViewall">Bold values are significant at &#60;&#8239;0&#46;05 level&#46;</p>"
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Glu&#47;Glu Group&#44; n&#8239;&#61;&#8239;66&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Glu&#47;Lys&#44; n&#8239;&#61;&#8239;32&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">t &#47;z &#47;</span> &#967; <span class="elsevierStyleItalic"><span class="elsevierStyleSup">2</span></span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Age&#44; years&#44; mean&#8239;&#177;&#8239;SD <a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;4&#8239;&#177;&#8239;1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;445&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The age-onset of SSD&#44; years&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;0&#8239;&#177;&#8239;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;3&#8239;&#177;&#8239;1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-0&#46;1 <a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;897&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Duration of untreated illness&#44; weeks&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#46;0&#8239;&#177;&#8239;42&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;7&#8239;&#177;&#8239;63&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;2<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;808&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age at the time of diagnosis&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;6&#8239;&#177;&#8239;1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;0&#8239;&#177;&#8239;1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&#46;4 <a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;168&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;418&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;36&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;28&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42 &#40;63&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23 &#40;71&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Family history of psychosis&#44; n &#40;&#37;&#41; <a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;31&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;31&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;991&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Family history of bipolar disorder <a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;6&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;659&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any substance use n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;15&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 &#40;40&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;005</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PANSS Scores&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Total PANSS score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">102&#46;6&#8239;&#177;&#8239;19&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#46;3&#8239;&#177;&#8239;20&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;7<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;494&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Total positive subscale score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;4&#8239;&#177;&#8239;7&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;4&#8239;&#177;&#8239;8&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;2<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;867&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Total negative subscale score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#46;1&#8239;&#177;&#8239;8&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;0&#8239;&#177;&#8239;7&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;6<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Val&#47;Val Group&#44; n&#8239;&#61;&#8239;74&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Age&#44; years&#44; mean&#8239;&#177;&#8239;SD <a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;504&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">The age-onset of SSD&#44; years&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8722;0&#46;6 <a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;573&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Duration of untreated illness&#44; weeks&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;0&#46;2 <a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;829&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Age at the time of diagnosis&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">15&#46;7&#8239;&#177;&#8239;1&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16&#46;1&#8239;&#177;&#8239;1&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;0&#46;9 <a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;358&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Sex&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8 &#40;32&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">17 &#40;68&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Family history of psychotic disorder&#44; n &#40;&#37;&#41; <a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;32&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">6 &#40;25&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;475&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Family history of bipolar disorder&#44; n &#40;&#37;&#41; <a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4 &#40;6&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2 &#40;8&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;652&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any substance use&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;23&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;28&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;612&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">PANSS Scores&#44; mean&#8239;&#177;&#8239;SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Total PANSS score&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">101&#46;9&#8239;&#177;&#8239;18&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">99&#46;8&#8239;&#177;&#8239;18&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;0&#46;7 <a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;491&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">27&#46;9&#8239;&#177;&#8239;8&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8722;0&#46;1 <a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;882&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Total negative subscale score&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">28&#46;6&#8239;&#177;&#8239;8&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">24&#46;6&#8239;&#177;&#8239;5&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#8722;2&#46;4 <a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Total general psychopathology subscale score&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">46&#46;4&#8239;&#177;&#8239;10&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">47&#46;8&#8239;&#177;&#8239;10&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;0&#46;4 <a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;710&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Val&#47;Met genotype <a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;368&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;5 - 7&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glu&#47;Lys genotype <a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;5 &#8211; 15&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Val&#47;Met &#42; Glu&#47;Lys genotype <a class="elsevierStyleCrossRefs" href="#tblfn0035"><span class="elsevierStyleSup">a&#44;b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;389&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0 &#8211; 3&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Glu&#47;Glu genotype was the reference category for DRD2&#47;ANKK1 Taq1A polymorphism&#46;</p>"
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          ]
        ]
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The results of the logistic regression analysis for the presence of substance abuse&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:65 [
            0 => array:3 [
              "identificador" => "bib0005"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The neurodevelopmental model of schizophrenia&#58; update 2005"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;L&#46; Rapoport"
                            1 => "A&#46;M&#46; Addington"
                            2 => "S&#46; Frangou"
                            3 => "M&#46;R&#46;C&#46; Psych"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.mp.4001642"
                      "Revista" => array:7 [
                        "tituloSerie" => "Mol Psychiatry&#46;"
                        "fecha" => "2005"
                        "volumen" => "10"
                        "numero" => "5"
                        "paginaInicial" => "434"
                        "paginaFinal" => "449"
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Article information
ISSN: 02136163
Original language: English
DOI:10.1016/j.ejpsy.2021.04.002
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