The moderating role of COMT gene rs4680 polymorphism between maladaptive metacognitive beliefs and negative symptoms in patients with schizophrenia

The moderating role of COMT gene rs4680 polymorphism between maladaptive metacognitive beliefs and negative symptoms in patients with schizophrenia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The moderating role of COMT gene rs4680 polymorphism between maladaptive metacognitive beliefs and negative symptoms in patients with schizophrenia Feten Fekih-Romdhane, Georges Kerbage, Nagham Hachem, Michelle El Murr, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4606067/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Nov, 2024 Read the published version in BMC Psychiatry → Version 1 posted 10 You are reading this latest preprint version Abstract Background: Although the positive association between impairments in metacognitive capacity and negative symptoms in people with schizophrenia spectrum disorders is widely evidenced in the literature, the explaining mechanisms of this association are still less known and poorly understood. This study aims to bridge this knowledge gap by testing the hypothesis that COMT rs4680 variants will act as moderators in the relationship between certain metacognitive domains and negative symptoms’ severity. Method: A cross-sectional study was carried-out during the period between February and March 2024. A total of 115 biologically unrelated Arab (Lebanese) patients with schizophrenia (mean age of 57.52 ± 10.35 years, 63.5% males) were included. Results: After controlling for sex and duration of illness as a potential confounder, moderation analyses showed that the AG genotype of the COMT rs4680 served as a significant moderator between maladaptive metacognitions about cognitive confidence and negative symptoms. In non-carriers of the COMT rs4680 AG genotype, greater endorsement of lack of cognitive confidence is significantly associated with greater negative symptoms. Conclusion: Findings suggest that metacognition may be a relevant treatment target in the management of negative symptoms particularly in non-carriers of the COMT rs4680 AG genotype. Therefore, genetic testing could potentially be used to match patients with metacognitive interventions that are more likely to be effective in supporting recovery from negative symptoms. Metacognition Negative symptoms COMT gene rs4680 Schizophrenia. Figures Figure 1 INTRODUCTION Negative symptoms are a group of symptoms that reflect a loss of normal functions that are normally present—they include social withdrawal, lack of motivation, flattened emotion, alogia, and anhedonia [ 1 ]. They are commonly reported in schizophrenia, with over 50% of patients showing at least one negative symptom [ 2 , 3 ]. Negative symptoms are defined by the DSM-5 as one of the key dimensions of schizophrenia [ 4 ]. They can be a persistent clinical problem for patients [ 5 ], and lead to severe disability [ 6 ] and lower rates of recovery [ 7 ], thus posing a substantial burden on patients, their relatives, the healthcare system and society. Despite their detrimental impact, negative symptoms remain to date generally unresponsive to treatment. Their identification and treatment are more challenging compared to positive symptoms [ 8 ], making them yet neglected targets for treatment [ 9 ]. Previous efforts dedicated to improving negative symptom treatments have been hampered by incomplete understanding of the mechanisms that lead to their development and maintenance [ 10 ]. Therefore, there is a clear need to enhance knowledge on the mechanisms underlying the formation and evolution of negative symptoms [ 11 ]. One potential theoretical mechanism accounting for the emergence and persistence of negative symptoms is disturbed metacognition [ 12 ]. The relationship between metacognition and negative symptoms Metacognition, broadly defined as ‘thinking about thinking’, is often conceptualized as a multidimensional construct encompassing five core domains: 1) the belief that it is important to control one’s thoughts, especially distressing thoughts (i.e. need to control thoughts); 2) worrying understood as uncontrollable or dangerous activity (i.e. uncontrollability and danger); 3) worrying helps one to avoid future problems (i.e. Positive Beliefs about worry); 4) overthinking about one’s own thoughts (i.e. Cognitive Self-Consciousness), and 5) beliefs concerning cognitive confidence (i.e. lack of confidence in memory) [ 13 ]. There is strong evidence to support that people diagnosed with schizophrenia exhibit global metacognitive deficits that are far more pronounced than in healthy controls [ 14 ] or people with other severe medical (e.g., Human Immunodeficiency Virus [ 15 ]) and psychiatric conditions (e.g., bipolar disorder [ 16 ], depression [ 17 ], posttraumatic stress disorder [ 18 ], borderline personality disorder [ 19 ]). There is a growing amount of literature which suggests that impaired overall metacognitive functioning exhibited by individuals with psychosis is closely connected to negative symptoms. A meta-analysis by Arnon-Ribenfeld et al. [ 20 ] indicated a significant positive association between metacognition impairment and symptomatic outcomes, and emphasized the negative effect of this association on social quality of life. Particularly, many studies conducted in different clinical settings and nations showed that metacognitive abilities are negatively related to more severe negative symptoms in people with schizophrenia spectrum disorders (e.g., [ 16 , 21 , 22 ]). Several prior studies also showed that a worse efficiency in metacognitive skills from 6 to 36 months after baseline assessment was predictive of greater negative symptoms (e.g., [ 23 , 24 ]). An individual participant data meta-analysis including 21 data sets and 1301 people with psychosis observed a strong relationship between metacognition and summed scores of negative symptoms that was not overridden by duration of illness or disorganization, albeit it was concluded that “this relationship is more complex than is evident” [ 25 ]. More recently, a systematic review confirmed this statement, by pointing to mixed evidence and unclear relationship between disrupted metacognition and negative symptoms, with only half of the included studies having reported statistically significant findings [ 11 ]. Overall, although the positive association between impairments in metacognitive capacity and negative symptoms in people with schizophrenia spectrum disorders is widely evidenced in the literature, the underlying mechanisms of this association are still poorly understood. To date, limited theories and models have emerged as attempts to explain the pathways leading from metacognition abilities to negative symptoms. It has been proposed that metacognition may be implicated in negative symptoms by generating a fragmented comprehension of others' and one's own beliefs, intentions, and desires, which can lead, in turn, to diminished motivation secondary to a decline of the ability to reflect on what is of importance and worth pursuing. For instance, uncertainty over the intentions of others can cause discomfort and negatively impact interpersonal relationships, thereby contributing to avoidance of social interactions and a tendency to withdraw [ 26 , 27 ]. Difficulties experienced in giving meaning to one’s or others’ thoughts of themselves may contribute to increased challenges in the identification of goals and the initiation of action towards them [ 28 ]. The present study proposes to contribute to the reduction of a knowledge gap regarding the mechanisms behind the relationship between metacognition and negative symptoms by investigating a new genetic factor that might be involved as a moderator, i.e. the Catechol-O-Methyltransferase (COMT) gene rs4680 polymorphism. COMT gene rs4680 polymorphism as moderator The COMT is a key modulator of dopaminergic transmission in the prefrontal cortex (PFC) [ 29 ]. COMT genes have multiple single nucleotide polymorphisms (SNPs), with the most commonly studied one being the rs4680 (Val/Met or G/A substitution)[ 30 ]. Because of its catalytic activity for dopamine degradation, genetic variation of the COMT has long been thought to confer susceptibility to schizophrenia and, more specifically, contribute to negative symptoms. Indeed, dysfunction of the COMT rs4680 polymorphism affects the thermostability of the mature protein, altering dopamine levels in various regions of the brain, particularly in the PFC. As the G allele is a predominant factor of higher COMT activity in the PFC, it causes a reduction in synaptic dopamine level and a disrupted prefrontal function [ 31 ]. The presence of the G allele was found to be linked to schizophrenia [ 32 ], to impairments in neuronal and cognition functions [ 33 ] and structural brain abnormalities [ 34 ] in individuals with schizophrenia. These rs4680-related alterations in brain volumes are known to be implicated in negative symptoms of schizophrenia [ 35 ]. Several studies showed a significant association between negative symptoms in schizophrenia and COMT rs4680 polymorphism. For example, the SNP rs4680 (Val/Met) present in the COMT gene showed significant association with blunted affect in a sample of unrelated Chinese individuals diagnosed with schizophrenia [ 36 ]. Madzarac et al. [ 37 ] found that the presence of the G allele or GG genotype of COMT rs4680 was associated with an increase in several dimensions of negative symptoms and anhedonia in Croatian female patients with schizophrenia. On the other hand, since dopamine is essential in prefrontal functions, rs4680 was claimed as a key factor influencing cognitive abilities. Moreover, the COMT rs4680 polymorphism has also an important role in modulating noradrenergic neurotransmission [ 38 ], which regulate many aspects of cognition [ 39 ]. Both dopamine and noradrenaline are likely to affect metacognition [ 40 ]. The rs4680 SNP in the COMT gene is linked to decreased COMT activity and higher levels of dopaminergic stimulation of postsynaptic neurons [ 31 ], which was related to greater performance in PFC-dependent tasks, such as executive cognitive function [ 41 ], attention and cognitive flexibility [ 42 ], as well as working memory [ 43 ]. In addition, the Met-allele is linked to successful outcomes in financial decision-making [ 44 ], which requires the integrity of metacognitive processes. Findings from studies in schizophrenia-spectrum disorders indicated that genetic variability in the COMT gene was associated with cognitive functions [ 33 , 45 ] and differential improvement in cognition following cognitive intervention [ 46 , 47 ]. Studies specifically focusing on the COMT rs4680 (Val/Met) polymorphism showed that Val carriers exert decreased baseline cognitive abilities, whereas Met carriers show more improvement in cognitive performance after cognitive remediation [ 48 ]. Based on the aforementioned literature, it can be hypothesized that schizophrenia patients carrying certain genotypes of COMT rs4680 would have an increased likelihood of developing more severe negative symptoms under the influence of maladaptive metacognitive beliefs. Rationale of this study This study was designed to specifically address several gaps in the current knowledge regarding the relationships between metacognition and negative symptoms in schizophrenia. This can be crucial to further understand the mechanisms behind the development and maintenance of negative symptoms [ 11 ]. The first identified knowledge gap is scarcity of research that has specifically focused on the relationship between metacognition and negative symptoms, with negative symptoms being often measured as a covariate rather than an outcome measure [ 11 ]. Additionally, most of the previous studies on the topic had some measurement limitations, making conclusions questionable [ 25 ]—as negative symptoms were often measured by the PANSS rather than by more focused and modern tools [ 49 , 50 ]. Moreover, earlier studies have mainly considered total scores across multiple domains of metacognition. Since metacognition is multidimensional in nature, it is important to explore whether each metacognitive subdomain has a unique influence on negative symptoms [ 51 ]. Finally, no studies have investigated the role of genetic variation in the relationship between metacognition and negative symptoms. By doing this in a genetically under-represented population of patients with schizophrenia of the Middle East, our study may significantly add to the existing body of knowledge regarding the interplay between metacognitive capacities and negative symptoms across genetically diverse individuals. The present study aims to test the hypothesis that COMT rs4680 variants will act as moderators in the relationship between certain metacognitive domains and negative symptoms’ severity. METHODS Sample and procedure This cross-sectional study has been conducted during February and March 2024. The target sample was set as inpatients of the Psychiatric Hospital of the Cross, Jal Eddib (suburbs of the capital Beirut), Lebanon, with the following inclusion criteria: (1) age of 18 years and over, (2) with a schizophrenia disorder diagnosis following the DSM-5 criteria [ 35 ], (3) at chronic stage of the disease, defined as with more than 1 year of illness duration [ 52 ], and institutionalized in the above-mentioned long-stay hospital for more than one year (detailed description of the study population can be found elsewhere [ 53 , 54 ]), (4) remitted and clinically stable (as defined by Fleischhacker et al. [ 55 ], patients “were required to be symptomatically stable, as judged by the treating physician, be receiving a stable dose of an antipsychotic drug for at least 4 weeks before the survey and be in good general physical health”). A total of 115 biologically unrelated Arab (Lebanese) patients with schizophrenia were included. Genotyping To analyze the rs4680 polymorphism of the COMT gene, Thermo Scientific GeneJET Genomic DNA Purification Kit (Thermo Fisher Scientific Inc.) was used to isolate DNA from patients’ blood. DNA quantification was done using the NanoDrop spectrophotometer (Thermo Fisher Scientific Inc.). For all SNP genotyping, The TaqMan® Drug Metabolism Genotyping Assay (ABI: Applied Biosystems Inc., Foster City, CA, USA) was used according to the standard manufacturer’s protocol. DNA samples of known genotypes were used in every reaction as positive controls. The PCR reaction was conducted in a 25 µl reaction volume, containing 11.25 µl DNA sample (20ng), 12.5 µl PCR master mix, and 1.25µl primer pairs and probes. A pre-incubation at 95°C for 10 min was used to activate the Hot-Start DNA polymerase and denature DNA. It was followed by 50 amplification cycles consisting of a denaturation phase at 92°C for 15 Sec and an extension phase at 60°C for 90 Sec. The probe fluorescence signal was detected using the Bio-Rad CFX96 Real-Time PCR System. Measures Sociodemographic and clinical information Data were gathered during a face-to-face interview of around 30 minutes with all participants. The questionnaire consisted of a first section containing information on socio-demographics, including age, gender, education level (Primary, secondary, university), marital status (single, married, separated, divorced, widowed), duration of illness (in years), and duration of hospitalization (in years). The Self-evaluation of Negative Symptoms scale (SNS) The SNS is a 20-item scale that assesses negative symptoms through five dimensions: emotional withdrawal, social withdrawal, avolition, alogia, and anhedonia [ 56 ]. Each item is scored on a three-point Likert-type scale, ranging from 0 (strongly disagree) to 2 (strongly agree). Higher total scores (0–40) reflect more severe negative symptoms. The Arabic version of the SNS was used [ 57 ], with a Cronbach alpha value of.85. The 30-item Metacognitions Questionnaire (MCQ-30) The MCQ-30 is composed of 30 items that evaluate maladaptive metacognitive beliefs through five domains: Negative beliefs, Cognitive self-consciousness, Need to control thoughts, Positive beliefs about worry, and (Lack of) Cognitive confidence [ 13 ]. Each item is rated on a four-point Likert scale from 1 (Disagree) to 4 (Agree). Higher total sub-scores refer to greater level of the corresponding domain. The Arabic validated version of the MCQ-30 was used in this study [ 58 ]. It yielded a Cronbach alpha ranging from .72 to .97 for the different sub-scores in the present sample. Analytic Strategy The SPSS software v.26 was used for the statistical analysis. The impulsivity score was considered normally distributed, with normality verified since the skewness and kurtosis values for each item of the scale varied between − 1 and + 1 [ 59 ]. Student’s t-test was used to compare two means, the ANOVA test to compare three means, and the Pearson test to correlate the impulsivity scores with other continuous variables. The moderation analysis was conducted using PROCESS MACRO (an SPSS add-on) v.3.4 model 1, taking the polymorphism rs4680 as a moderator between emotional intelligence and impulsivity. Interaction terms were probed by examining the association of one predictor with impulsivity at the mean, 1 SD below the mean and 1 SD above the mean of the moderator. Results were adjusted over all variables that showed a p < 0.25 in the bivariate analysis. P < 0.05 was deemed statistically significant. RESULTS One hundred fifteen patients enrolled in the study, with a mean age of 57.52 ± 10.35 years and 63.5% males. Other characteristics of the patients are summarized in Table 1 . Table 1 Sociodemographic and other characteristics of the patients (n = 115) Gender Male 73 (63.5%) Female 42 (36.5%) Education Primary 28 (24.3%) Complementary 43 (37.4%) Secondary 30 (26.1%) University 14 (12.2%) Cigarette smoking No 28 (24.3%) Yes 87 (75.7%) Cannabis lifetime use No 105 (91.3%) Yes 10 (8.7%) Rs4680 polymorphism🟃 Genotype AA 34 (32.1%) Genotype AG 44 (41.5%) Genotype GG 28 (26.4%) Age (years) 57.64 ± 10.41 Age at onset of schizophrenia 25.32 ± 7.76 Duration of hospitalization (years) 3.73 ± 4.82 Duration of illness (years) 32.17 ± 11.54 Impulsivity 22.70 ± 4.08 Emotional intelligence 37.93 ± 8.42 🟃Numbers do not add the total N because of missing values. Bivariate analysis Significantly higher negative symptoms scores were found in females compared to males (Table 2 ). Moreover, higher cognitive confidence was significantly associated with higher negative symptoms (Table 3). Table 2 Bivariate analysis of factors associated with negative symptoms (SNS scale score). Mean ± SD t / F df /df1,df2 p Sex -5.36 111 < .001 Male 9.63 ± 6.44 Female 16.61 ± 7.04 Education 1.86 3,109 .141 Primary 14.70 ± 8.42 Complementary 11.43 ± 7.05 Secondary 12.17 ± 7.28 University 9.43 ± 6.10 Cigarette smoking 1.15 111 .253 No 13.59 ± 7.48 Yes 11.71 ± 7.42 Cannabis lifetime use .96 111 .339 No 12.37 ± 7.40 Yes 10.00 ± 7.94 Rs4680 polymorphism .48 2,102 .618 Genotype AA 11.67 ± 7.41 Genotype AG 13.20 ± 6.78 Genotype GG 11.86 ± 8.61 Numbers in bold indicate significant p values. Table 3. Pearson correlation matrix. 1 2 3 4 5 6 7 8 9 10 1. Negative symptoms (SNS scores) 1 2. Age .08 1 3. Age of schizophrenia onset .11 .17 1 4. Duration of hospitalization .01 .07 − .17 1 5. Duration of illness .03 .73*** − .46*** .04 1 6. Cognitive confidence .34*** − .01 .06 − .13 − .01 − .35*** 1 7. Positive beliefs − .02 − .30** − .19* .01 − .20* − .07 .03 1 8. Cognitive self-consciousness − .18 − .14 − .03 .15 − .15 .39*** − .35*** .20* 1 9. Negative beliefs 0.13 − .22* − .18 − .09 − .07 − .17 .06 .43*** .15 1 10. Needs to control thoughts − .08 − .23* .06 .07 − .25** .28** − .04 .21* .31** .36*** *p < .05; **p < .01; ***p < .001 Moderation analysis The results of the moderation analyses are shown in Table 4 . After controlling for sex and duration of illness, the interaction of cognitive confidence by rs4680 genotype AG was significantly associated with negative symptoms. In patients not having the rs4680 genotype AG, higher cognitive confidence was significantly associated with higher negative symptoms (Fig. 1 ). Table 4 Moderation analysis. a. Genotype AG vs AA* b. Genotype GG vs AA* Beta t p 95% CI Beta t p 95% CI Model 2: Cognitive confidence as an independent variable Cognitive confidence .47 3.42 .001 .20; .75 .23 1.74 .085 − .03; .49 Genotype 7.57 2.60 .011 1.79; 13.35 -3.34 -1.01 .316 -9.91; 3.23 Interaction cognitive confidence by genotype − .49 -2.23 .028 − .92; − .05 .20 .83 .408 − .28; .68 Model 3: Positive beliefs as an independent variable Positive beliefs .03 .19 .852 − .29; .35 − .16 -1.16 .249 − .44; .12 Genotype 5.84 1.94 .055 − .13; 11.98 -2.20 − .62 .538 -9.25; 4.85 Interaction positive beliefs by genotype − .37 -1.53 .128 − .84; .11 .13 .44 .664 − .45; .70 Model 4: Cognitive self-consciousness as an independent variable Cognitive self-consciousness − .29 -1.64 .104 − .64; .06 − .21 -1.36 .176 − .52; .10 Genotype − .68 − .13 .895 -10.77; 9.42 1.11 .18 .861 -11.34; 13.55 Interaction cognitive self-consciousness by genotype .13 .47 .638 − .43; .69 − .10 − .28 .780 − .77; .58 Model 5: Negative beliefs as an independent variable Negative beliefs .17 1.03 .307 − .16; .50 − .001 − .01 .995 − .32; .32 Genotype 4.97 1.56 .121 -1.33; 11.27 -2.60 − .75 .452 -9.43; 4.23 Interaction negative beliefs by genotype − .33 -1.15 .255 − .89; .24 .20 .62 .537 − .44; .84 Model 6: Need to control thoughts as an independent variable Need to control thoughts − .01 − .05 .959 − .41; .39 − .34 -1.83 .070 − .71; .03 Genotype 9.87 2.21 .030 .99; 18.74 -6.53 -1.33 .185 -16.24; 3.18 Interaction Need to control thoughts by genotype − .58 -1.87 .064 -1.20; .04 .42 1.22 .225 − .26; 1.10 *Reference group; numbers in bold indicate significant p values. DISCUSSION This is the first study investigating the moderating role of the COMT rs4818 polymorphism in the relationship between metacognition and negative symptoms and after controlling for possible confounders, the first examination of this relationship using a specific measure of negative symptoms and considering each metacognition domain separately, and the first inclusion of people diagnosed with schizophrenia originating from an Arab country of the Middle East. Moderation analyses showed that, in our patients with schizophrenia, the AG genotype of the COMT rs4680 served as a significant moderator between maladaptive metacognitions about cognitive confidence and negative symptoms. After controlling for sex and duration of illness as a potential confounder, our results showed that the COMT rs4680 AG genotype significantly moderated the relationship between a specific maladaptive metacognitive belief, i.e. the lack of cognitive confidence, and negative symptoms. This metacognitive dimension refers to a distrust of one's perception, attention, and memory. Consistent with our results, previous studies indicated that low cognitive confidence is more frequently exhibited by people at risk of developing psychosis compared to healthy controls [ 60 , 61 ]. In addition, evidence drawn from an extensive literature supports that impaired metacognition is associated with greater negative symptoms in people with schizophrenia spectrum disorders [ 16 , 21 , 22 , 62 – 66 ]. However, when considering each metacognition subdomain separately in relation to summed measures of negative symptoms, findings show more inconsistencies, with around or below 50% significance observed across studies for all metacognition subdomains [ 11 ]. Indeed, in agreement with our findings, previously reported relationships between metacognition subscales and negative symptoms found a range of significant and non-significant associations [ 66 , 67 ]. This calls into question whether considering metacognition as a single-scored construct could obscure the differential relationships of its subtypes with negative symptoms, and suggests that future studies need to examine the different metacognitive domains and how each of these might impact negative symptoms before drawing any clear conclusion about this relationship [ 11 ]. The study hypothesis was partly supported, showing a significant moderating effect of the COMT rs4680 AG genotype on the association between lack of cognitive confidence and negative symptoms. In non-carriers of the COMT rs4680 AG genotype, greater endorsement of lack of cognitive confidence is significantly associated with greater negative symptoms. The COMT rs4680 genotype is one of the major enzymes involved in noradrenaline [ 38 ] and dopamine [ 29 ] metabolism in the PFC, which have both been implicated in metacognition [ 40 , 68 ]. This finding is consistent with previous research that genetic variations in the COMT gene are closely connected to cognition [ 33 , 45 , 69 ] and to response to cognitive interventions [ 46 , 47 ] in patients with schizophrenia spectrum disorders. Altogether, the current results suggest that COMT genotype may improve our understanding of the development and maintenance of negative symptoms, and inform the tailoring of interventions for effectively relieving them in schizophrenia-spectrum patients. Study limitations There are some limitations to be recognized and addressed in future studies. First, the design was cross-sectional, which prevents from concluding that metacognitive beliefs contributed to the development of patients’ negative symptoms. Future studies with a longitudinal design may confirm the causal investigation of these variables. Second, the study included chronic inpatients who were in a long-stay and under antipsychotic treatment, which can limit the representativeness of our sample. Further studies including outpatients, those in acute phases, and those at earlier stages of the disease are needed before conclusions can be generalized to all patients diagnosed with schizophrenia. Clinical implications and future research directions These limitations aside, our study has valuable practical implications. The findings showed that COMT rs4680 moderated the relationship between metacognition and negative symptoms. Particularly, patients with schizophrenia who do not carry the SNP COMT rs4680 AG genotype were more likely to be affected by metacognition impairments (i.e. a lack of cognitive confidence) and produce more severe negative symptoms. This suggests that integrated intervention and prevention programs that consider both genetic and individual cognitive factors simultaneously are needed to improve negative symptoms in schizophrenia. Our analyses provide more evidence to support the significant relationship between metacognition and negative symptom scores, which calls for further development and evaluation of treatments targeting maladaptive metacognitive beliefs in people with severe and/or persistent negative symptoms [ 25 ]. An example of interventions that can be tested in our context and population is the Metacognitive Reflection and Insight Therapy (MERIT)s [ 70 ], which demonstrated effectiveness in improving metacognitive functioning and reducing symptoms in persons with schizophrenia [ 71 – 73 ]. In addition, it is suggested that metacognition may be a relevant treatment target in the management of negative symptoms particularly in non-carriers of the COMT rs4680 AG genotype. Therefore, genetic testing could potentially be used to match patients with metacognitive interventions that are more likely to be effective in supporting recovery from negative symptoms. CONCLUSION This study sought to advance our comprehension of the intricate nature and mechanisms underlying the relationship between metacognition and negative symptoms. Findings indicated that the role of the COMT gene rs4680 polymorphism in moderating this relationship was supported. This suggests that genetic testing can pave the way for more effective and personalized interventions, tailored to the unique needs of each patient based on their metacognitive and genetic profile. In particular, interventions targeting metacognition, while taking various COMT genotypes into account, may fill a gap in treatment needs of patients with negative symptoms, and facilitate efforts towards improvements in clinical and functional outcomes. Future experimental genomic studies are warranted to confirm our findings. Declarations Ethics Approval and Consent to Participate: Ethics approval for this study was obtained from the ethics committee at the Psychiatric Hospital of the Cross. A digital informed consent was obtained from all subjects and/or their legal guardians for study participation and was considered equivalent to receiving a written informed consent. All methods were performed in accordance with the relevant guidelines and regulations. Consent for publication: Not applicable. Availability of data and materials: All data generated or analyzed during this study are not publicly available due the restrictions from the ethics committee. Reasonable requests can be addressed to the corresponding author (SH). Competing interests: The authors have nothing to disclose. Funding: None. Author contributions: FFR, EEH, AAL and SH designed the study; FFR drafted the manuscript; GK, NH and MEM collected the data; SH carried out the analysis and interpreted the results; all authors reviewed the paper for intellectual content, reviewed the final manuscript and gave their consent. Acknowledgements: The authors would like to thank all participants. References Strauss GP, Nuñez A, Ahmed AO, Barchard KA, Granholm E, Kirkpatrick B, Gold JM, Allen DN: The latent structure of negative symptoms in schizophrenia . JAMA psychiatry 2018, 75 (12):1271-1279. Sicras-Mainar A, Maurino J, Ruiz-Beato E, Navarro-Artieda R: Impact of negative symptoms on healthcare resource utilization and associated costs in adult outpatients with schizophrenia: a population-based study . BMC psychiatry 2014, 14 (1):1-8. 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The British Journal of Psychiatry 2005, 187 (2):131-136. Dollfus S, Mach C, Morello R: Self-evaluation of negative symptoms: a novel tool to assess negative symptoms . Schizophrenia Bulletin 2016, 42 (3):571-578. Hajj A, Hallit S, Chamoun K, Sacre H, Obeid S, Haddad C, Dollfus S, Rabbaa Khabbaz L: Validation of the Arabic version of the “self-evaluation of negative symptoms” scale (SNS) . BMC psychiatry 2020, 20 (1):1-8. Fekih-Romdhane F, Azzi V, Obeid S, Gerges S, Sarray El Dine A, Malaeb D, Soufia M, Hallit S: Psychometric properties of an Arabic translation of the short form of the metacognition questionnaire (MCQ-30) in a non-clinical adult sample . BMC psychiatry 2023, 23 (1):795. Hair Jr JF, Sarstedt M, Ringle CM, Gudergan SP: Advanced issues in partial least squares structural equation modeling : saGe publications; 2017. Morrison AP, French P, Wells A: Metacognitive beliefs across the continuum of psychosis: Comparisons between patients with psychotic disorders, patients at ultra-high risk and non-patients . Behaviour research and therapy 2007, 45 (9):2241-2246. Barkus E, Stirling J, French P, Morrison A, Bentall R, Lewis S: Distress and metacognition in psychosis prone individuals: comparing high schizotypy to the at-risk mental state . The Journal of nervous and mental disease 2010, 198 (2):99-104. Vohs JL, Lysaker P, Francis M, Hamm J, Buck K, Olesek K, Outcalt J, Dimaggio G, Leonhardt B, Liffick E: Metacognition, social cognition, and symptoms in patients with first episode and prolonged psychoses . Schizophrenia Research 2014, 153 (1-3):54-59. WeiMing W, Yi D, Lysaker P, Kai W: The relationship among the metacognitive ability, empathy and psychotic symptoms in schizophrenic patients in a post-acute phase of illness . Chinese Journal of Behavioral Medicine and Brain Science 2015, 24 (2):128-131. Lysaker PH, Carcione A, Dimaggio G, Johannesen J, Nicolò G, Procacci M, Semerari A: Metacognition amidst narratives of self and illness in schizophrenia: associations with neurocognition, symptoms, insight and quality of life . Acta psychiatrica scandinavica 2005, 112 (1):64-71. Nicolo G, Dimaggio G, Popolo R, Carcione A, Procacci M, Hamm J, Buck KD, Pompili E, Buccione I, Lagrotteria B: Associations of metacognition with symptoms, insight, and neurocognition in clinically stable outpatients with schizophrenia . The Journal of nervous and mental disease 2012, 200 (7):644-647. MacBeth A, Gumley A, Schwannauer M, Carcione A, McLeod HJ, Dimaggio G: Metacognition in first episode psychosis: item level analysis of associations with symptoms and engagement . Clinical psychology & psychotherapy 2016, 23 (4):329-339. Mitchell LJ, Gumley A, Reilly ES, Macbeth A, Lysaker P, Carcione A, Dimaggio G: Metacognition in forensic patients with schizophrenia and a past history of interpersonal violence: an exploratory study . Psychosis 2012, 4 (1):42-51. Lak A, Nomoto K, Keramati M, Sakagami M, Kepecs A: Midbrain dopamine neurons signal belief in choice accuracy during a perceptual decision . Current Biology 2017, 27 (6):821-832. Loch AA, van de Bilt MT, Bio DS, Prado CM, de Sousa RT, Valiengo LL, Moreno RA, Zanetti MV, Gattaz WF: Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission . Braz J Psychiatry 2015, 37 (3):235-241. Lysaker PH, Buck KD, Leonhardt BL, Buck B, Hamm J, Hasson-Ohayon I, Vohs JL, Dimaggio G: Metacognitively focused psychotherapy for people with schizophrenia: Eight core elements that define practice . In: Social cognition and metacognition in schizophrenia. edn.: Elsevier; 2014: 195-213. Arnon-Ribenfeld N, Bloom R, Atzil-Slonim D, Peri T, de Jong S, Hasson-Ohayon I: Metacognitive Reflection and Insight Therapy (MERIT) among people with schizophrenia: lessons from two case studies . American Journal of Psychotherapy 2018, 71 (4):175-185. Buck KD, Lysaker PH: Addressing metacognitive capacity in the psychotherapy for schizophrenia: A case study . Clinical Case Studies 2009, 8 (6):463-472. Hillis JD, Leonhardt BL, Vohs JL, Buck KD, Salvatore G, Popolo R, Dimaggio G, Lysaker PH: Metacognitive reflective and insight therapy for people in early phase of a schizophrenia spectrum disorder . Journal of Clinical Psychology 2015, 71 (2):125-135. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4606067","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":324626364,"identity":"27f82067-e448-4ec0-9d0e-c4681c6bf62d","order_by":0,"name":"Feten Fekih-Romdhane","email":"","orcid":"","institution":"Tunis El Manar University","correspondingAuthor":false,"prefix":"","firstName":"Feten","middleName":"","lastName":"Fekih-Romdhane","suffix":""},{"id":324626365,"identity":"162cd6a2-20b1-48ae-814c-cb0db84b1068","order_by":1,"name":"Georges Kerbage","email":"","orcid":"","institution":"Holy Spirit University of 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13:03:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4606067/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4606067/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12888-024-06275-0","type":"published","date":"2024-11-20T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60614514,"identity":"cf7c6056-4d35-4d8c-9f5c-3050c9caffae","added_by":"auto","created_at":"2024-07-18 20:04:01","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":144456,"visible":true,"origin":"","legend":"\u003cp\u003eModeration of the effect of the Metacognition domain “Cognitive confidence” on negative symptoms by the COMT rs4680 genotypes\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4606067/v1/6b45410c6c82e624f9131a6a.jpeg"},{"id":69834906,"identity":"3df7d939-5c06-4ae6-bb82-0811373428ff","added_by":"auto","created_at":"2024-11-25 16:10:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3154148,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4606067/v1/caa05d1a-2019-43e3-9392-f4fa450fe9db.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The moderating role of COMT gene rs4680 polymorphism between maladaptive metacognitive beliefs and negative symptoms in patients with schizophrenia","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eNegative symptoms are a group of symptoms that reflect a loss of normal functions that are normally present\u0026mdash;they include social withdrawal, lack of motivation, flattened emotion, alogia, and anhedonia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. They are commonly reported in schizophrenia, with over 50% of patients showing at least one negative symptom [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Negative symptoms are defined by the DSM-5 as one of the key dimensions of schizophrenia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. They can be a persistent clinical problem for patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and lead to severe disability [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and lower rates of recovery [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], thus posing a substantial burden on patients, their relatives, the healthcare system and society. Despite their detrimental impact, negative symptoms remain to date generally unresponsive to treatment. Their identification and treatment are more challenging compared to positive symptoms [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], making them yet neglected targets for treatment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Previous efforts dedicated to improving negative symptom treatments have been hampered by incomplete understanding of the mechanisms that lead to their development and maintenance [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, there is a clear need to enhance knowledge on the mechanisms underlying the formation and evolution of negative symptoms [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. One potential theoretical mechanism accounting for the emergence and persistence of negative symptoms is disturbed metacognition [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eThe relationship between metacognition and negative symptoms\u003c/h3\u003e\n\u003cp\u003eMetacognition, broadly defined as \u0026lsquo;thinking about thinking\u0026rsquo;, is often conceptualized as a multidimensional construct encompassing five core domains: 1) the belief that it is important to control one\u0026rsquo;s thoughts, especially distressing thoughts (i.e. need to control thoughts); 2) worrying understood as uncontrollable or dangerous activity (i.e. uncontrollability and danger); 3) worrying helps one to avoid future problems (i.e. Positive Beliefs about worry); 4) overthinking about one\u0026rsquo;s own thoughts (i.e. Cognitive Self-Consciousness), and 5) beliefs concerning cognitive confidence (i.e. lack of confidence in memory) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. There is strong evidence to support that people diagnosed with schizophrenia exhibit global metacognitive deficits that are far more pronounced than in healthy controls [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] or people with other severe medical (e.g., Human Immunodeficiency Virus [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]) and psychiatric conditions (e.g., bipolar disorder [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], depression [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], posttraumatic stress disorder [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], borderline personality disorder [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]). There is a growing amount of literature which suggests that impaired overall metacognitive functioning exhibited by individuals with psychosis is closely connected to negative symptoms.\u003c/p\u003e \u003cp\u003eA meta-analysis by Arnon-Ribenfeld et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] indicated a significant positive association between metacognition impairment and symptomatic outcomes, and emphasized the negative effect of this association on social quality of life. Particularly, many studies conducted in different clinical settings and nations showed that metacognitive abilities are negatively related to more severe negative symptoms in people with schizophrenia spectrum disorders (e.g., [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]). Several prior studies also showed that a worse efficiency in metacognitive skills from 6 to 36 months after baseline assessment was predictive of greater negative symptoms (e.g., [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]). An individual participant data meta-analysis including 21 data sets and 1301 people with psychosis observed a strong relationship between metacognition and summed scores of negative symptoms that was not overridden by duration of illness or disorganization, albeit it was concluded that \u0026ldquo;this relationship is more complex than is evident\u0026rdquo; [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. More recently, a systematic review confirmed this statement, by pointing to mixed evidence and unclear relationship between disrupted metacognition and negative symptoms, with only half of the included studies having reported statistically significant findings [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOverall, although the positive association between impairments in metacognitive capacity and negative symptoms in people with schizophrenia spectrum disorders is widely evidenced in the literature, the underlying mechanisms of this association are still poorly understood. To date, limited theories and models have emerged as attempts to explain the pathways leading from metacognition abilities to negative symptoms. It has been proposed that metacognition may be implicated in negative symptoms by generating a fragmented comprehension of others' and one's own beliefs, intentions, and desires, which can lead, in turn, to diminished motivation secondary to a decline of the ability to reflect on what is of importance and worth pursuing. For instance, uncertainty over the intentions of others can cause discomfort and negatively impact interpersonal relationships, thereby contributing to avoidance of social interactions and a tendency to withdraw [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Difficulties experienced in giving meaning to one\u0026rsquo;s or others\u0026rsquo; thoughts of themselves may contribute to increased challenges in the identification of goals and the initiation of action towards them [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The present study proposes to contribute to the reduction of a knowledge gap regarding the mechanisms behind the relationship between metacognition and negative symptoms by investigating a new genetic factor that might be involved as a moderator, i.e. the Catechol-O-Methyltransferase (COMT) gene rs4680 polymorphism.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCOMT gene rs4680 polymorphism as moderator\u003c/h2\u003e \u003cp\u003eThe COMT is a key modulator of dopaminergic transmission in the prefrontal cortex (PFC) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. COMT genes have multiple single nucleotide polymorphisms (SNPs), with the most commonly studied one being the rs4680 (Val/Met or G/A substitution)[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Because of its catalytic activity for dopamine degradation, genetic variation of the COMT has long been thought to confer susceptibility to schizophrenia and, more specifically, contribute to negative symptoms. Indeed, dysfunction of the COMT rs4680 polymorphism affects the thermostability of the mature protein, altering dopamine levels in various regions of the brain, particularly in the PFC. As the G allele is a predominant factor of higher COMT activity in the PFC, it causes a reduction in synaptic dopamine level and a disrupted prefrontal function [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The presence of the G allele was found to be linked to schizophrenia [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], to impairments in neuronal and cognition functions [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] and structural brain abnormalities [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] in individuals with schizophrenia. These rs4680-related alterations in brain volumes are known to be implicated in negative symptoms of schizophrenia [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Several studies showed a significant association between negative symptoms in schizophrenia and COMT rs4680 polymorphism. For example, the SNP rs4680 (Val/Met) present in the COMT gene showed significant association with blunted affect in a sample of unrelated Chinese individuals diagnosed with schizophrenia [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Madzarac et al. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] found that the presence of the G allele or GG genotype of COMT rs4680 was associated with an increase in several dimensions of negative symptoms and anhedonia in Croatian female patients with schizophrenia.\u003c/p\u003e \u003cp\u003eOn the other hand, since dopamine is essential in prefrontal functions, rs4680 was claimed as a key factor influencing cognitive abilities. Moreover, the COMT rs4680 polymorphism has also an important role in modulating noradrenergic neurotransmission [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], which regulate many aspects of cognition [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Both dopamine and noradrenaline are likely to affect metacognition [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The rs4680 SNP in the COMT gene is linked to decreased COMT activity and higher levels of dopaminergic stimulation of postsynaptic neurons [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], which was related to greater performance in PFC-dependent tasks, such as executive cognitive function [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], attention and cognitive flexibility [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], as well as working memory [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In addition, the Met-allele is linked to successful outcomes in financial decision-making [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], which requires the integrity of metacognitive processes. Findings from studies in schizophrenia-spectrum disorders indicated that genetic variability in the COMT gene was associated with cognitive functions [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e] and differential improvement in cognition following cognitive intervention [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Studies specifically focusing on the COMT rs4680 (Val/Met) polymorphism showed that Val carriers exert decreased baseline cognitive abilities, whereas Met carriers show more improvement in cognitive performance after cognitive remediation [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Based on the aforementioned literature, it can be hypothesized that schizophrenia patients carrying certain genotypes of COMT rs4680 would have an increased likelihood of developing more severe negative symptoms under the influence of maladaptive metacognitive beliefs.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRationale of this study\u003c/h3\u003e\n\u003cp\u003eThis study was designed to specifically address several gaps in the current knowledge regarding the relationships between metacognition and negative symptoms in schizophrenia. This can be crucial to further understand the mechanisms behind the development and maintenance of negative symptoms [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The first identified knowledge gap is scarcity of research that has specifically focused on the relationship between metacognition and negative symptoms, with negative symptoms being often measured as a covariate rather than an outcome measure [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, most of the previous studies on the topic had some measurement limitations, making conclusions questionable [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u0026mdash;as negative symptoms were often measured by the PANSS rather than by more focused and modern tools [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Moreover, earlier studies have mainly considered total scores across multiple domains of metacognition. Since metacognition is multidimensional in nature, it is important to explore whether each metacognitive subdomain has a unique influence on negative symptoms [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Finally, no studies have investigated the role of genetic variation in the relationship between metacognition and negative symptoms. By doing this in a genetically under-represented population of patients with schizophrenia of the Middle East, our study may significantly add to the existing body of knowledge regarding the interplay between metacognitive capacities and negative symptoms across genetically diverse individuals. The present study aims to test the hypothesis that COMT rs4680 variants will act as moderators in the relationship between certain metacognitive domains and negative symptoms\u0026rsquo; severity.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSample and procedure\u003c/h2\u003e \u003cp\u003eThis cross-sectional study has been conducted during February and March 2024. The target sample was set as inpatients of the Psychiatric Hospital of the Cross, Jal Eddib (suburbs of the capital Beirut), Lebanon, with the following inclusion criteria: (1) age of 18 years and over, (2) with a schizophrenia disorder diagnosis following the DSM-5 criteria [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], (3) at chronic stage of the disease, defined as with more than 1 year of illness duration [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e], and institutionalized in the above-mentioned long-stay hospital for more than one year (detailed description of the study population can be found elsewhere [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]), (4) remitted and clinically stable (as defined by Fleischhacker et al. [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e], patients \u0026ldquo;were required to be symptomatically stable, as judged by the treating physician, be receiving a stable dose of an antipsychotic drug for at least 4 weeks before the survey and be in good general physical health\u0026rdquo;). A total of 115 biologically unrelated Arab (Lebanese) patients with schizophrenia were included.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGenotyping\u003c/h3\u003e\n\u003cp\u003eTo analyze the rs4680 polymorphism of the COMT gene, Thermo Scientific GeneJET Genomic DNA Purification Kit (Thermo Fisher Scientific Inc.) was used to isolate DNA from patients\u0026rsquo; blood. DNA quantification was done using the NanoDrop spectrophotometer (Thermo Fisher Scientific Inc.).\u003c/p\u003e \u003cp\u003eFor all SNP genotyping, The TaqMan\u0026reg; Drug Metabolism Genotyping Assay (ABI: Applied Biosystems Inc., Foster City, CA, USA) was used according to the standard manufacturer\u0026rsquo;s protocol. DNA samples of known genotypes were used in every reaction as positive controls. The PCR reaction was conducted in a 25 \u0026micro;l reaction volume, containing 11.25 \u0026micro;l DNA sample (20ng), 12.5 \u0026micro;l PCR master mix, and 1.25\u0026micro;l primer pairs and probes. A pre-incubation at 95\u0026deg;C for 10 min was used to activate the Hot-Start DNA polymerase and denature DNA. It was followed by 50 amplification cycles consisting of a denaturation phase at 92\u0026deg;C for 15 Sec and an extension phase at 60\u0026deg;C for 90 Sec. The probe fluorescence signal was detected using the Bio-Rad CFX96 Real-Time PCR System.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMeasures\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eSociodemographic and clinical information\u003c/h2\u003e \u003cp\u003e Data were gathered during a face-to-face interview of around 30 minutes with all participants. The questionnaire consisted of a first section containing information on socio-demographics, including age, gender, education level (Primary, secondary, university), marital status (single, married, separated, divorced, widowed), duration of illness (in years), and duration of hospitalization (in years).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eThe Self-evaluation of Negative Symptoms scale (SNS)\u003c/h2\u003e \u003cp\u003eThe SNS is a 20-item scale that assesses negative symptoms through five dimensions: emotional withdrawal, social withdrawal, avolition, alogia, and anhedonia [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Each item is scored on a three-point Likert-type scale, ranging from 0 (strongly disagree) to 2 (strongly agree). Higher total scores (0\u0026ndash;40) reflect more severe negative symptoms. The Arabic version of the SNS was used [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e], with a Cronbach alpha value of.85.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eThe 30-item Metacognitions Questionnaire (MCQ-30)\u003c/h2\u003e \u003cp\u003eThe MCQ-30 is composed of 30 items that evaluate maladaptive metacognitive beliefs through five domains: Negative beliefs, Cognitive self-consciousness, Need to control thoughts, Positive beliefs about worry, and (Lack of) Cognitive confidence [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Each item is rated on a four-point Likert scale from 1 (Disagree) to 4 (Agree). Higher total sub-scores refer to greater level of the corresponding domain. The Arabic validated version of the MCQ-30 was used in this study [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. It yielded a Cronbach alpha ranging from .72 to .97 for the different sub-scores in the present sample.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAnalytic Strategy\u003c/h2\u003e \u003cp\u003eThe SPSS software v.26 was used for the statistical analysis. The impulsivity score was considered normally distributed, with normality verified since the skewness and kurtosis values for each item of the scale varied between \u0026minus;\u0026thinsp;1 and +\u0026thinsp;1 [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Student\u0026rsquo;s t-test was used to compare two means, the ANOVA test to compare three means, and the Pearson test to correlate the impulsivity scores with other continuous variables. The moderation analysis was conducted using PROCESS MACRO (an SPSS add-on) v.3.4 model 1, taking the polymorphism rs4680 as a moderator between emotional intelligence and impulsivity. Interaction terms were probed by examining the association of one predictor with impulsivity at the mean, 1 SD below the mean and 1 SD above the mean of the moderator. Results were adjusted over all variables that showed a \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.25 in the bivariate analysis. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was deemed statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eOne hundred fifteen patients enrolled in the study, with a mean age of 57.52\u0026thinsp;\u0026plusmn;\u0026thinsp;10.35 years and 63.5% males. Other characteristics of the patients are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSociodemographic and other characteristics of the patients (n\u0026thinsp;=\u0026thinsp;115)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e73 (63.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42 (36.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (24.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplementary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43 (37.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30 (26.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUniversity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (12.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCigarette smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (24.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e87 (75.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCannabis lifetime use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e105 (91.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (8.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRs4680 polymorphism\u0026#128963;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34 (32.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype AG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44 (41.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (26.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e57.64\u0026thinsp;\u0026plusmn;\u0026thinsp;10.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset of schizophrenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25.32\u0026thinsp;\u0026plusmn;\u0026thinsp;7.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of hospitalization (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.73\u0026thinsp;\u0026plusmn;\u0026thinsp;4.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of illness (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32.17\u0026thinsp;\u0026plusmn;\u0026thinsp;11.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImpulsivity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.70\u0026thinsp;\u0026plusmn;\u0026thinsp;4.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmotional intelligence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37.93\u0026thinsp;\u0026plusmn;\u0026thinsp;8.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u0026#128963;Numbers do not add the total N because of missing values.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eBivariate analysis\u003c/h2\u003e \u003cp\u003eSignificantly higher negative symptoms scores were found in females compared to males (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Moreover, higher cognitive confidence was significantly associated with higher negative symptoms (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBivariate analysis of factors associated with negative symptoms (SNS scale score).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003et / F\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003edf /df1,df2\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.63\u0026thinsp;\u0026plusmn;\u0026thinsp;6.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e16.61\u0026thinsp;\u0026plusmn;\u0026thinsp;7.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3,109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.70\u0026thinsp;\u0026plusmn;\u0026thinsp;8.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplementary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.43\u0026thinsp;\u0026plusmn;\u0026thinsp;7.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.17\u0026thinsp;\u0026plusmn;\u0026thinsp;7.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUniversity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.43\u0026thinsp;\u0026plusmn;\u0026thinsp;6.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCigarette smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.253\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.59\u0026thinsp;\u0026plusmn;\u0026thinsp;7.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.71\u0026thinsp;\u0026plusmn;\u0026thinsp;7.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCannabis lifetime use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.339\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.37\u0026thinsp;\u0026plusmn;\u0026thinsp;7.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.00\u0026thinsp;\u0026plusmn;\u0026thinsp;7.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRs4680 polymorphism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2,102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.618\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype AA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.67\u0026thinsp;\u0026plusmn;\u0026thinsp;7.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype AG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.20\u0026thinsp;\u0026plusmn;\u0026thinsp;6.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype GG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.86\u0026thinsp;\u0026plusmn;\u0026thinsp;8.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNumbers in bold indicate significant \u003cem\u003ep\u003c/em\u003e values.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;3. Pearson correlation matrix.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Negative symptoms (SNS scores)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Age of schizophrenia onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. Duration of hospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. Duration of illness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.73***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.46***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6. Cognitive confidence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.34***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.35***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7. Positive beliefs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.30**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.19*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.20*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8. Cognitive self-consciousness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.39***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.35***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e.20*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9. Negative beliefs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.22*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e.43***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10. Needs to control thoughts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.23*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.25**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.28**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e.21*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e.31**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e.36***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003e*p\u0026thinsp;\u0026lt;\u0026thinsp;.05; **p\u0026thinsp;\u0026lt;\u0026thinsp;.01; ***p\u0026thinsp;\u0026lt;\u0026thinsp;.001\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eModeration analysis\u003c/h2\u003e \u003cp\u003eThe results of the moderation analyses are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e. After controlling for sex and duration of illness, the interaction of cognitive confidence by rs4680 genotype AG was significantly associated with negative symptoms. In patients not having the rs4680 genotype AG, higher cognitive confidence was significantly associated with higher negative symptoms (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eModeration analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003ea. Genotype AG vs AA*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eb. Genotype GG vs AA*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBeta\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003et\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBeta\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003et\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eModel 2: Cognitive confidence as an independent variable\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCognitive confidence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.20; .75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.03; .49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.79; 13.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-3.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-9.91; 3.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteraction cognitive confidence by genotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.028\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.92; \u0026minus;\u0026thinsp;.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.28; .68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel 3: Positive beliefs as an independent variable\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive beliefs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.852\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.29; .35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.44; .12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.13; 11.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-9.25; 4.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteraction positive beliefs by genotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.84; .11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.664\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.45; .70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel 4: Cognitive self-consciousness as an independent variable\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCognitive self-consciousness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.64; .06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.52; .10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.895\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-10.77; 9.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-11.34; 13.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteraction cognitive self-consciousness by genotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.638\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.43; .69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.780\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.77; .58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel 5: Negative beliefs as an independent variable\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative beliefs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.307\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.16; .50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.995\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.32; .32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1.33; 11.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-9.43; 4.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteraction negative beliefs by genotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.89; .24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.537\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.44; .84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eModel 6: Need to control thoughts as an independent variable\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeed to control thoughts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.959\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.41; .39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.71; .03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.030\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.99; 18.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-6.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.185\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-16.24; 3.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteraction Need to control thoughts by genotype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1.20; .04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;.26; 1.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e*Reference group; numbers in bold indicate significant \u003cem\u003ep\u003c/em\u003e values.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis is the first study investigating the moderating role of the COMT rs4818 polymorphism in the relationship between metacognition and negative symptoms and after controlling for possible confounders, the first examination of this relationship using a specific measure of negative symptoms and considering each metacognition domain separately, and the first inclusion of people diagnosed with schizophrenia originating from an Arab country of the Middle East. Moderation analyses showed that, in our patients with schizophrenia, the AG genotype of the COMT rs4680 served as a significant moderator between maladaptive metacognitions about cognitive confidence and negative symptoms.\u003c/p\u003e \u003cp\u003eAfter controlling for sex and duration of illness as a potential confounder, our results showed that the COMT rs4680 AG genotype significantly moderated the relationship between a specific maladaptive metacognitive belief, i.e. the lack of cognitive confidence, and negative symptoms. This metacognitive dimension refers to a distrust of one's perception, attention, and memory. Consistent with our results, previous studies indicated that low cognitive confidence is more frequently exhibited by people at risk of developing psychosis compared to healthy controls [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. In addition, evidence drawn from an extensive literature supports that impaired metacognition is associated with greater negative symptoms in people with schizophrenia spectrum disorders [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR63 CR64 CR65\" citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. However, when considering each metacognition subdomain separately in relation to summed measures of negative symptoms, findings show more inconsistencies, with around or below 50% significance observed across studies for all metacognition subdomains [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Indeed, in agreement with our findings, previously reported relationships between metacognition subscales and negative symptoms found a range of significant and non-significant associations [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. This calls into question whether considering metacognition as a single-scored construct could obscure the differential relationships of its subtypes with negative symptoms, and suggests that future studies need to examine the different metacognitive domains and how each of these might impact negative symptoms before drawing any clear conclusion about this relationship [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe study hypothesis was partly supported, showing a significant moderating effect of the COMT rs4680 AG genotype on the association between lack of cognitive confidence and negative symptoms. In non-carriers of the COMT rs4680 AG genotype, greater endorsement of lack of cognitive confidence is significantly associated with greater negative symptoms. The COMT rs4680 genotype is one of the major enzymes involved in noradrenaline [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and dopamine [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] metabolism in the PFC, which have both been implicated in metacognition [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. This finding is consistent with previous research that genetic variations in the COMT gene are closely connected to cognition [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e] and to response to cognitive interventions [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] in patients with schizophrenia spectrum disorders. Altogether, the current results suggest that COMT genotype may improve our understanding of the development and maintenance of negative symptoms, and inform the tailoring of interventions for effectively relieving them in schizophrenia-spectrum patients.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eThere are some limitations to be recognized and addressed in future studies. First, the design was cross-sectional, which prevents from concluding that metacognitive beliefs contributed to the development of patients\u0026rsquo; negative symptoms. Future studies with a longitudinal design may confirm the causal investigation of these variables. Second, the study included chronic inpatients who were in a long-stay and under antipsychotic treatment, which can limit the representativeness of our sample. Further studies including outpatients, those in acute phases, and those at earlier stages of the disease are needed before conclusions can be generalized to all patients diagnosed with schizophrenia.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eClinical implications and future research directions\u003c/h2\u003e \u003cp\u003eThese limitations aside, our study has valuable practical implications. The findings showed that COMT rs4680 moderated the relationship between metacognition and negative symptoms. Particularly, patients with schizophrenia who do not carry the SNP COMT rs4680 AG genotype were more likely to be affected by metacognition impairments (i.e. a lack of cognitive confidence) and produce more severe negative symptoms. This suggests that integrated intervention and prevention programs that consider both genetic and individual cognitive factors simultaneously are needed to improve negative symptoms in schizophrenia. Our analyses provide more evidence to support the significant relationship between metacognition and negative symptom scores, which calls for further development and evaluation of treatments targeting maladaptive metacognitive beliefs in people with severe and/or persistent negative symptoms [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. An example of interventions that can be tested in our context and population is the Metacognitive Reflection and Insight Therapy (MERIT)s [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e], which demonstrated effectiveness in improving metacognitive functioning and reducing symptoms in persons with schizophrenia [\u003cspan additionalcitationids=\"CR72\" citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. In addition, it is suggested that metacognition may be a relevant treatment target in the management of negative symptoms particularly in non-carriers of the COMT rs4680 AG genotype. Therefore, genetic testing could potentially be used to match patients with metacognitive interventions that are more likely to be effective in supporting recovery from negative symptoms.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis study sought to advance our comprehension of the intricate nature and mechanisms underlying the relationship between metacognition and negative symptoms. Findings indicated that the role of the COMT gene rs4680 polymorphism in moderating this relationship was supported. This suggests that genetic testing can pave the way for more effective and personalized interventions, tailored to the unique needs of each patient based on their metacognitive and genetic profile. In particular, interventions targeting metacognition, while taking various COMT genotypes into account, may fill a gap in treatment needs of patients with negative symptoms, and facilitate efforts towards improvements in clinical and functional outcomes. Future experimental genomic studies are warranted to confirm our findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval for this study was obtained\u0026nbsp;from the ethics committee at the Psychiatric Hospital of the Cross. A digital informed consent was obtained from all subjects and/or their legal guardians for study participation and was considered equivalent to receiving a written informed consent. All methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are not publicly available due the restrictions from the ethics committee. Reasonable requests can be addressed to the corresponding author (SH).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFFR, EEH, AAL and SH designed the study; FFR drafted the manuscript; GK, NH and MEM collected the data; SH carried out the analysis and interpreted the results; all authors reviewed the paper for intellectual content, reviewed the final manuscript and gave their consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all participants.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStrauss GP, Nu\u0026ntilde;ez A, Ahmed AO, Barchard KA, Granholm E, Kirkpatrick B, Gold JM, Allen DN: \u003cstrong\u003eThe latent structure of negative symptoms in schizophrenia\u003c/strong\u003e. \u003cem\u003eJAMA psychiatry \u003c/em\u003e2018, \u003cstrong\u003e75\u003c/strong\u003e(12):1271-1279.\u003c/li\u003e\n\u003cli\u003eSicras-Mainar A, Maurino J, Ruiz-Beato E, Navarro-Artieda R: \u003cstrong\u003eImpact of negative symptoms on healthcare resource utilization and associated costs in adult outpatients with schizophrenia: a population-based study\u003c/strong\u003e. \u003cem\u003eBMC psychiatry \u003c/em\u003e2014, \u003cstrong\u003e14\u003c/strong\u003e(1):1-8.\u003c/li\u003e\n\u003cli\u003eBobes J, Arango C, Garcia-Garcia M, Rejas J: \u003cstrong\u003ePrevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS study\u003c/strong\u003e. \u003cem\u003eThe Journal of clinical psychiatry \u003c/em\u003e2009, \u003cstrong\u003e70\u003c/strong\u003e(3):15446.\u003c/li\u003e\n\u003cli\u003eMalaspina D, Walsh-Messinger J, Gaebel W, Smith LM, Gorun A, Prudent V, Antonius D, Tr\u0026eacute;meau F: \u003cstrong\u003eNegative symptoms, past and present: a historical perspective and moving to DSM-5\u003c/strong\u003e. \u003cem\u003eEuropean Neuropsychopharmacology \u003c/em\u003e2014, \u003cstrong\u003e24\u003c/strong\u003e(5):710-724.\u003c/li\u003e\n\u003cli\u003eSauv\u0026eacute; 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\u003cstrong\u003eEpistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission\u003c/strong\u003e. \u003cem\u003eBraz J Psychiatry \u003c/em\u003e2015, \u003cstrong\u003e37\u003c/strong\u003e(3):235-241.\u003c/li\u003e\n\u003cli\u003eLysaker PH, Buck KD, Leonhardt BL, Buck B, Hamm J, Hasson-Ohayon I, Vohs JL, Dimaggio G: \u003cstrong\u003eMetacognitively focused psychotherapy for people with schizophrenia: Eight core elements that define practice\u003c/strong\u003e. In: \u003cem\u003eSocial cognition and metacognition in schizophrenia.\u003c/em\u003e edn.: Elsevier; 2014: 195-213.\u003c/li\u003e\n\u003cli\u003eArnon-Ribenfeld N, Bloom R, Atzil-Slonim D, Peri T, de Jong S, Hasson-Ohayon I: \u003cstrong\u003eMetacognitive Reflection and Insight Therapy (MERIT) among people with schizophrenia: lessons from two case studies\u003c/strong\u003e. \u003cem\u003eAmerican Journal of Psychotherapy \u003c/em\u003e2018, \u003cstrong\u003e71\u003c/strong\u003e(4):175-185.\u003c/li\u003e\n\u003cli\u003eBuck KD, Lysaker PH: \u003cstrong\u003eAddressing metacognitive capacity in the psychotherapy for schizophrenia: A case study\u003c/strong\u003e. \u003cem\u003eClinical Case Studies \u003c/em\u003e2009, \u003cstrong\u003e8\u003c/strong\u003e(6):463-472.\u003c/li\u003e\n\u003cli\u003eHillis JD, Leonhardt BL, Vohs JL, Buck KD, Salvatore G, Popolo R, Dimaggio G, Lysaker PH: \u003cstrong\u003eMetacognitive reflective and insight therapy for people in early phase of a schizophrenia spectrum disorder\u003c/strong\u003e. \u003cem\u003eJournal of Clinical Psychology \u003c/em\u003e2015, \u003cstrong\u003e71\u003c/strong\u003e(2):125-135.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Metacognition, Negative symptoms, COMT gene, rs4680, Schizophrenia.","lastPublishedDoi":"10.21203/rs.3.rs-4606067/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4606067/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Although the positive association between impairments in metacognitive capacity and negative symptoms in people with schizophrenia spectrum disorders is widely evidenced in the literature, the explaining mechanisms of this association are still less known and poorly understood. This study aims to bridge this knowledge gap by testing the hypothesis that COMT rs4680 variants will act as moderators in the relationship between certain metacognitive domains and negative symptoms’ severity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod:\u003c/strong\u003e A cross-sectional study was carried-out during the period between February and March 2024. A total of 115 biologically unrelated Arab (Lebanese) patients with schizophrenia (mean age of 57.52 ± 10.35 years, 63.5% males) were included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After controlling for sex and duration of illness as a potential confounder, moderation analyses showed that the AG genotype of the COMT rs4680 served as a significant moderator between maladaptive metacognitions about cognitive confidence and negative symptoms. In non-carriers of the COMT rs4680 AG genotype, greater endorsement of lack of cognitive confidence is significantly associated with greater negative symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Findings suggest that metacognition may be a relevant treatment target in the management of negative symptoms particularly in non-carriers of the COMT rs4680 AG genotype. Therefore, genetic testing could potentially be used to match patients with metacognitive interventions that are more likely to be effective in supporting recovery from negative symptoms.\u003c/p\u003e","manuscriptTitle":"The moderating role of COMT gene rs4680 polymorphism between maladaptive metacognitive beliefs and negative symptoms in patients with schizophrenia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 20:03:56","doi":"10.21203/rs.3.rs-4606067/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-26T20:09:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-24T21:08:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-08T15:35:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"147431089168892611229939047723470367048","date":"2024-08-07T21:59:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70952966564276269815871927937203324666","date":"2024-08-07T10:02:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-29T06:45:31+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-03T12:19:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-20T14:56:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-20T14:55:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2024-06-19T13:02:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e006af4a-4651-48be-92b3-f1f6e1660d47","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-25T16:01:46+00:00","versionOfRecord":{"articleIdentity":"rs-4606067","link":"https://doi.org/10.1186/s12888-024-06275-0","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2024-11-20 15:57:32","publishedOnDateReadable":"November 20th, 2024"},"versionCreatedAt":"2024-07-18 20:03:56","video":"","vorDoi":"10.1186/s12888-024-06275-0","vorDoiUrl":"https://doi.org/10.1186/s12888-024-06275-0","workflowStages":[]},"version":"v1","identity":"rs-4606067","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4606067","identity":"rs-4606067","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}