Long-term benzodiazepine use is associated with poorer cognitive function in schizophrenia: Findings from the SALT-C cohort

Long-term benzodiazepine use is associated with poorer cognitive function in schizophrenia: Findings from the SALT-C cohort | 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 Long-term benzodiazepine use is associated with poorer cognitive function in schizophrenia: Findings from the SALT-C cohort Caiping Liu, Lei Zhang, Qiyang Pan, Yue Shi, Wenjuan Yu, Guanjun Li, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8797752/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background The association between long-term use of benzodiazepines (BDZs) and cognitive function in patients with schizophrenia has not been fully characterized. This study aimed to investigate the relationship between long-term BDZs use and cognitive impairment in schizophrenia. Methods Data were derived from an observational study of treatment with atypical antipsychotics in Chinese patients with schizophrenia (SALT-C). Fifty-seven patients with long-term use of BDZs (≥ 60 days) were included, and 57 BDZs non-users were matched using propensity scores for age, sex, disease duration, and atypical antipsychotics received. Cognitive impairment was assessed using the Montreal Cognitive Assessment (MoCA); psychotic symptoms, illness severity, and psychosocial functioning were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale. Between-group comparisons were performed using independent-samples t-tests or Mann–Whitney U tests. Multivariate analysis was performed using binary logistic regression. Results The long-term BDZs user group showed a significantly lower total MoCA score [16.02 (6.69)] than the BDZs non-user group [19.33 (7.11)] (P = 0.012). No significant between-group differences were observed in total scores on the PANSS, CGI-S, or PSP (all P > 0.05). Long-term BDZs use was independently associated with cognitive impairment (OR = 7.728, P = 0.017), whereas years of education was negatively associated with cognitive impairment (OR = 0.740, P = 0.007). Conclusions Long-term BDZs use is associated with poorer cognitive performance in patients with schizophrenia, suggesting that cognitive function should be monitored during BDZs treatment in this population. Benzodiazepines schizophrenia long-term use cognitive function atypical antipsychotics Figures Figure 1 Figure 2 Introduction Cognitive impairment is recognized as a core feature of schizophrenia, including deficits in working memory, executive function, attention, and processing speed, affecting approximately 75–80% of patients to varying degrees [ 1 – 4 ]. Given that these deficits are linked to impaired social functioning in domains such as community integration, occupational competence, and daily skill acquisition, cognitive dysfunction has been widely recognized as a major determinant of long-term outcome in schizophrenia [ 5 – 9 ]. The pathogenesis of cognitive impairment is complex. Current evidence implicates a combination of genetic vulnerability, cortical excitation-inhibition (E/I) imbalance, and dysregulation of neurotransmitters involving dopamine, glutamate, and gamma-aminobutyric acid (GABA) [ 10 ]. Several studies have indicated that pharmacological treatment also plays a crucial role in the progression of cognitive impairment observed in schizophrenia [ 11 , 12 ]. Given the role of GABAergic dysfunction in cognitive processes, medications targeting the GABA system, particularly benzodiazepines (BDZs), may have clinically relevant effects on cognition in schizophrenia. The cognitive benefits of currently available psychotropic medications are limited [ 13 ]. Moreover, some treatments, such as conventional antipsychotics, may worsen cognitive impairment in schizophrenia [ 14 ]. Meanwhile, there is growing concern about the effects of BDZs on cognitive function in schizophrenia. BDZs represent one of the most frequently used adjunctive pharmacotherapies in patients with schizophrenia, and are widely used for various therapeutic purposes, including the management of anxiety and sleep disturbances, the mitigation of antipsychotic side effects, and rapid tranquilization [ 15 ]. In the CATIE trial, the co-prescription rate of BDZs was approximately 22%. Notably, another study demonstrated that once initiated, long-term use was highly prevalent, with cumulative treatment duration exceeding one year in up to 62.9% of schizophrenia patients [ 16 ]. Although BDZs are considered safe and effective for short-term use, their potential for long-term cognitive impact remains a concern. In non-psychotic patients, long-term BDZs use is often associated with broad cognitive deficits [ 17 ]. A recent meta-analysis has confirmed this association, although the severity of impairment and the specific cognitive domains involved vary considerably [ 18 ]. The underlying mechanisms for BDZ‑induced cognitive impairment may involve the acute enhancement of GABA A receptor-mediated inhibitory neurotransmission [ 19 ]. This disruption of hippocampal and prefrontal cortical function can lead to deficits in working memory, executive function, and attention. Additionally, long‑term BDZs use may promote neuroplastic changes or receptor downregulation, further exacerbating cognitive decline [ 20 , 21 ]. However, it remains uncertain whether these mechanisms operate similarly in schizophrenia, given baseline cognitive impairment and altered GABAergic signaling. The cognitive effects of BDZs in schizophrenia remain debated. A cross-sectional study reported an association between BDZs use and poorer cognitive and social function in older adults (≥ 55 years) with schizophrenia, along with increased hospitalization duration and readmission rates [ 22 ]. Research on community-dwelling stabilized patients has shown that daily use of BDZs is associated with reduced working memory and attentional performance [ 23 ]. In contrast, a few studies have found no significant association between benzodiazepine use and cognitive function [ 24 ]. Moreover, research suggests that cognitive deficits associated with BDZs may be at least partially reversible. In a Japanese cohort of patients with schizophrenia, significant improvement in verbal memory was observed following gradual BDZs discontinuation [ 25 ]. Longitudinal studies have not consistently demonstrated progressive decline over time; some evidence suggests that cognitive deficits appear to stabilize after a certain duration of exposure [ 26 ]. These conflicting findings may be attributed to variations in study design, BDZs dosage, exposure duration, or the cognitive domains assessed. Thus, the real-world association between long-term BDZs use and cognitive function in schizophrenia has yet to be clearly characterized. Therefore, this study aimed to examine the association between long-term BDZs use and cognitive function in patients with schizophrenia using real-world data. Propensity score matching was applied to balance key clinical characteristics, allowing for a more robust assessment of the cognitive impact of long-term BDZs use in routine clinical practice. Methods Participants The data for this study were obtained from the SALT-C study, an observational study on safety and related factors of treatment with atypical antipsychotics in Chinese patients with schizophrenia [ 27 ]. Participants were recruited from the Shanghai Mental Health Center between 2016 and 2019. All participants were outpatients or inpatients aged 18 years or older with a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), confirmed independently by at least two attending psychiatrists. All participants were either receiving or planning to initiate atypical antipsychotic (AAP) treatment. The study protocol was approved by the Ethics Committee of the Shanghai Mental Health Center (2010-35). Based on this cohort, this analysis aimed to evaluate the association between long-term BDZs use and cognitive function. Participants were eligible for the long-term BDZs user group if they had been using BDZs at a stable dosage for at least 60 consecutive days prior to enrollment. Participants were eligible for the BDZs non-user group if they had no prior history of BDZs use. Patients were excluded if they had comorbid psychiatric disorders (including bipolar disorder, major depressive disorder, or substance-induced psychotic disorders); neurological diseases (such as epilepsy, Parkinson’s disease, stroke, or traumatic brain injury); severe physical illnesses; a history of substance abuse or dependence (except nicotine) within the preceding three months; intellectual disability or severe cognitive impairment that would preclude completion of cognitive assessments; refusal or inability to provide informed consent; concurrent participation in another clinical study; were deemed unsuitable by the investigator; were currently receiving electroconvulsive therapy (ECT) or modified ECT without convulsion; or were currently using nootropics or potent anticholinergic agents. Procedures Demographic and clinical data were collected, including age, gender, years of education, episode and duration of illness. Detailed medication information was recorded for all prescribed AAPs, and for concomitant medications such as antidepressants. Information on BDZs was recorded, including the specific type, initial prescription date, and duration of use. Long-term use was defined as continuous use exceeding 60 days. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) [ 28 ]. The MoCA assesses multiple cognitive domains, including attention and concentration, executive function, memory, language, visuospatial ability, abstract thinking, and orientation. The total score ranges from 0 to 30, with higher scores indicating better cognitive performance; a cutoff score of 26 was used, with scores ≥ 26 indicating no cognitive impairment and scores < 26 indicating cognitive impairment. Psychopathology was assessed using the total score and the positive, negative, and general psychopathology subscale scores of the Positive and Negative Syndrome Scale (PANSS) [ 29 ]. Illness severity and psychosocial functioning were evaluated using the Clinical Global Impression-Severity (CGI-S) scale and the Personal and Social Performance (PSP) scale [ 30 , 31 ]. All psychological assessments were conducted by trained psychiatrists, having completed standardized training for each scale and demonstrated inter-rater reliability prior to data collection. Statistical analysis Propensity score matching (PSM) was performed to reduce selection bias between the study groups. A 1:1 matching protocol was applied based on age, gender, illness duration, and type of AAPs. All statistical analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables following normal distribution were expressed as mean and standard deviation [M (SD)]; non-normally distributed data were expressed as median and interquartile range [M (P25, P75)]. Categorical and ordinal variables were summarized as frequencies and percentages. Between-group comparisons were performed using independent-samples t-tests or Mann–Whitney U tests. Multivariate analysis was performed using binary logistic regression. A two-tailed P-value < 0.05 was considered statistically significant. Results Demographic characteristics and propensity score matching Of 842 patients initially screened, 690 were included in the analysis, comprising 62 long-term BDZs users and 628 non-users (Fig. 1). Among patients treated with BDZs, 66.0% were long-term users. The most commonly prescribed BDZs were alprazolam, followed by clonazepam and lorazepam; other agents included oxazepam, estazolam, and diazepam. Before propensity score matching, significant differences were observed between the two groups in age, episode status (first episode vs. relapse), illness duration, and type of AAPs prescribed (all P < 0.05). After propensity score matching, 57 patients were retained in the long-term BDZs user group and the BDZs non-user group, respectively. There were no significant differences between the two groups in age, gender, years of education, patient type (outpatient vs. inpatient), schizophrenia subtype, episode status, illness duration, or type of AAPs (all P > 0.05), indicating adequate covariate balance. In the long-term BDZs user group, the commonly prescribed AAP was olanzapine (43.9%), followed by aripiprazole (17.5%). Similarly, in the BDZs non-user group, olanzapine was the most commonly prescribed AAP (45.6%), followed by aripiprazole (17.5%) (Table 1 ). Figure 1 Trial profile. Note BDZs: benzodiazepines; PSM: propensity score matching; MoCA: Montreal Cognitive Assessment. Table 1 Demographic characteristics. Before PSM After PSM Long-term BDZs users BDZs non-users Z/χ 2 P Long-term BDZs users BDZs non-users Z/χ 2 P (n = 62) (n = 628) (n = 57) (n = 57) Age 57.00(46.75,63.00) 53.00(37.00,60.00) -2.897 0.004 * 57.00(49.00,64.00) 57.00(48.00,63.00) -0.139 0.889 Gender 1.588 0.208 0.039 0.843 Male 40 (64.5%) 353 (56.2%) 37(64.9%) 38(66.7%) Female 22 (35.5%) 275 (43.8%) 20(35.1%) 19(33.3%) Years of education 9.00(8.00,12.00) 9.00(9.00,12.00) -1.253 0.201 9.00(8.00,12.00) 9.00(8.00,12.00) -0.382 0.703 Patient type 5.449 0.066 1.036 0.309 Outpatient 2 (3.2%) 84 (13.4%) 1 (1.8%) 3 (5.3%) Inpatient 60 (96.8%) 544 (86.6%) 56 (98.2%) 54 (94.7%) Schizophrenia subtype 7.877 0.096 1.345 0.718 Hebephrenic schizophrenia 0 (0.0%) 6 (0.9%) 0 (0.0%) 0 (0.0%) Catatonic schizophrenia 0 (0.0%) 6 (0.9%) 0 (0.0%) 0 (0.0%) Paranoid schizophrenia 20 (32.3%) 227 (36.1%) 18 (31.6%) 20 (35.1%) Undifferentiated schizophrenia 10 (16.1%) 43 (6.8%) 10 (17.5%) 8 (14.0%) Residual schizophrenia 32 (51.6%) 346 (55.1%) 29 (50.9%) 29 (50.9%) Episode 8.220 0.004 * 2.151 0.142 First-episode status 2 (3.2%) 108 (17.2%) 2 (3.5%) 6 (10.5%) Relapse status 60 (96.8%) 520 (82.8%) 55 (96.5%) 51 (89.5%) Illness duration 28.00(18.50,35.50) 22.50(10.00,30.00) -3.255 0.001 * 28.00(19.00,37.50) 28.00(17.00,35.50) -0.397 0.691 AAP 24.758 0.001 * 0.353 1.000 Quetiapine 1 (1.6%) 37 (5.9%) 1 (1.8%) 1 (1.8%) Olanzapine 28 (45.2%) 180 (28.7%) 25 (43.9%) 26 (45.6%) Risperidone 9 (14.5%) 143 (22.8%) 9 (15.8%) 9 (15.8%) Aripiprazole 10 (16.1%) 122 (19.4%) 10 (17.5%) 10 (17.5%) Ziprasidone 2 (3.2%) 8 (1.3%) 2 (3.5%) 1 (1.8%) Paliperidone 3 (9.4%) 14 (2.2%) 3 (5.3%) 3 (5.3%) Amisulpride 1 (1.6%) 30 (4.8%) 1 (1.8%) 1 (1.8%) Perospirone 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Clozapine 8 (12.9%) 94 (15.0%) 6 (10.5%) 6 (10.5%) BDZ Treatment duration (months) 31.00(10.70,48.00) 31.00(14.50,50.00) Note: Data are presented as number (percentage%) or median (interquartile range). PSM: propensity score matching; BDZs: benzodiazepines; AAP: atypical antipsychotic. * P < 0.05. Comparison of clinical symptoms and severity between groups The total PANSS score was 57.50 (49.00, 75.75) in the long-term BDZs user group and 55.00 (46.75, 70.25) in the BDZs non-user group, with no significant difference observed between the groups (P > 0.05). Similarly, no significant differences were observed between the groups in the PANSS positive, negative, or general psychopathology subscales (all P > 0.05). The CGI-S and PSP scores also showed no significant differences between groups (all P > 0.05), indicating comparable severity of clinical symptoms and social functioning (Table 2 ). Table 2 Comparison of clinical symptoms, severity, and social performance. Long-term BDZs users BDZs non-users Z P PANSS total score 57.50 (49.00,75.75) 55.00 (46.75,70.25) -0.969 0.333 PANSS-positive score 8.00 (7.00,16.00) 8.50 (7.00,12.00) -0.814 0.415 PANSS-negative score 19.00 (16.25,25.75) 20.00 (15.75,24.00) -0.509 0.610 PANSS-general psychopathology score 28.00 (24.00,36.00) 27.00 (22.00,35.00) -0.832 0.405 CGI-S score 4.00 (3.00,4.00) 3.00 (3.00,4.50) -0.571 0.568 PSP score 60.00 (40.00,70.50) 60.00(45.00,65.00) -0.216 0.829 Note: Data are presented as median (interquartile range). BDZs: benzodiazepines; PANSS: Positive and Negative Syndrome Scale; CGI-S: Clinical Global Impression-Severity Scale; PSP: Personal and Social Performance Scale. Comparison of cognitive function between groups The mean total MoCA score was significantly lower in the long-term BDZs user group [16.02 (6.69)] compared with the BDZs non-user group [19.33 (7.11); P = 0.012, t = 2.566]. Both groups scored below the cutoff of 26, indicating the presence of overall cognitive impairment. Analysis of MoCA subdomains showed significantly poorer performance in the long-term BDZs user group compared with the BDZs non-user group on visuospatial/executive function (P = 0.012, Z = -2.501), naming (P = 0.025, Z = -2.236), language (P = 0.032, Z = -2.139), and abstraction (P = 0.032, Z = -2.142). No significant differences were observed in attention, delayed recall, or orientation (all P > 0.05) (Table 3 ). Table 3 Comparison of cognitive function. Long-term BDZs users BDZs non-users t/Z P MoCA total score 16.02 (6.69) 19.33 (7.11) 2.566 0.012 * Visuospatial/executive 2.00 (1.00,3.00) 3.00 (1.50,4.00) -2.501 0.012 * Naming 2.00 (2.00,3.00) 3.00 (2.00,3.00) -2.236 0.025 * Attention 4.00 (3.00,5.00) 5.00 (3.00,6,00) -1.891 0.059 Language 0.00 (0.00,1.00) 1.00 (0.00,2.00) -2.139 0.032 * Abstraction 0.82 (0.83) 1.18 (0.87) -2.142 0.032 * Delayed recall 1.00 (0.00,2.00) 2.00 (0.00,2.50) -1.856 0.063 Orientation 6.00 (4.00,6.00) 6.00 (5.00,6.00) -1.547 0.122 Note: Data are presented as mean (SD) or median (interquartile range). BDZs: benzodiazepines; MoCA: Montreal Cognitive Assessment. * P < 0.05. Multivariate Regression Analysis on correlates of cognitive impairment A binary logistic regression model was constructed to assess factors associated with cognitive impairment. Normal cognition (MoCA ≥ 26) served as the reference category for the dependent variable. The model included the following independent variables: age, gender, years of education, illness duration, and long-term BDZs use, and showed good model fit (χ² = 3.088, P = 0.929). Among these variables, long-term BDZs use was independently associated with cognitive impairment (OR = 7.728, P = 0.017), whereas years of education was associated with cognitive impairment (OR = 0.740, P = 0.007), while age, gender, and duration of illness were not significantly associated with cognitive impairment (Fig. 2, Table 4 ). Figure 2 Correlates of cognitive impairment Note BDZs: benzodiazepines; OR: odds ratio. Table 4 Logistic Regression analysis of factors associated with cognitive function B SE Wald χ 2 P OR 95%CI C min C max Long-term BDZs use 2.045 0.853 5.745 0.017 * 7.728 1.452 41.135 Years of education -0.301 0.111 7.355 0.007 * 0.740 0.595 0.920 Age -0.014 0.036 0.148 0.700 0.986 0.920 1.058 Gender 0.509 0.794 0.410 0.522 1.663 0.351 7.892 Illness duration 0.059 0.041 2.013 0.156 1.061 0.978 1.150 Note: * P < 0.05. Discussion This real-world study explored the association between long-term BDZs use and cognitive function in patients with schizophrenia. The primary finding was that patients with long-term BDZs use demonstrated significantly poorer overall cognitive performance than BDZs non-users. Moreover, long-term BDZs use was independently associated with cognitive impairment, while years of education was negatively associated with cognitive impairment. Additionally, it was observed that the proportion of long-term users among BDZ users was relatively high. In this study, cognitive function was assessed using the MoCA, a widely used and sensitive screening tool for cognitive impairment that has been validated for detecting cognitive deficits in patients with schizophrenia [ 28 , 32 ]. Propensity score matching was applied to balance baseline characteristics and account for potential confounding factors between long-term BDZs users and non-users [ 33 ]. Patients with long-term BDZs use had lower total MoCA scores, with more pronounced deficits observed in naming, language, abstraction, and visuospatial/executive subdomains compared with non-users, indicating an association between long-term BDZs use and poorer performance in these cognitive domains. Similar associations have also been reported in the non-psychiatric population [ 34 ]. This finding aligns with the multicenter FACE-SZ study, which reported that among 407 clinically stable patients with schizophrenia, long-term BDZs use was significantly associated with impairments in verbal memory and working memory [ 23 ]. Similarly, previous research has reported lower scores on the Global Assessment of Functioning–Cognition in Schizophrenia (GAF-CogS) scale in patients with schizophrenia spectrum disorders receiving long-term BDZ therapy[ 35 ]. Despite methodological differences, impairments across multiple cognitive domains were identified, particularly in language and executive function. Moreover, the present study found that patients with long-term BDZs use performed worse in visuospatial and abstraction domains, which is consistent with previous findings [ 36 ]. Overall, these observations suggest an association between long-term BDZs use and deficits across multiple cognitive domains in patients with schizophrenia. Although some studies have suggested that long-term BDZs users present with more severe clinical symptoms [ 35 ], no significant between-group differences in clinical symptom severity or social functioning were observed in our sample. In the present study, multivariable logistic regression analysis indicated that long-term BDZs use was positively associated with cognitive impairment in patients with schizophrenia, whereas years of education were inversely associated with cognitive impairment. These findings further suggest long-term BDZs use independently associated with an increased cognitive impairment after adjustment for relevant covariates. Nevertheless, although long-term benzodiazepine use was associated with greater cognitive impairment (OR = 7.728), the relatively wide confidence interval indicates limited precision of the effect estimate. The limited sample size and heterogeneity in duration of BDZs use may contribute to this uncertainty. These results point to a possible risk trend, with the clinical significance requiring further investigation in larger, prospective studies. The association between years of education and cognitive impairment is consistent with the cognitive reserve hypothesis, whereby educational attainment could increase the tolerance to disease-related brain dysfunction [ 37 ]. Among all initially recruited patients prescribed BDZs, approximately two-thirds were identified as long-term users. The mean duration of BDZs use was 31 months, exceeding two years. Although the overall rate of BDZs co-prescription in the baseline dataset was lower than that reported in some previous studies, the proportion of long-term users was relatively high. This observation might be partially attributable to real-world prescribing practices, as suggested in previous study, whereby BDZ treatment, once initiated, tends to be maintained over extended periods in certain clinical settings [ 16 ]. Similar findings have been reported, with up to 62.9% of patients with schizophrenia exposed to BDZs for more than one year [ 38 ]. This interpretation remains uncertain and needs to be evaluated in longitudinal studies focusing on long-term BDZs prescribing practices and related clinical factors. Definitions of long-term use vary across studies, ranging from several months to years; the most common thresholds are continuous use for 3–12 months [ 23 , 35 , 39 , 40 ]. In the present study, long-term use was defined as continuous exposure for more than two months. This operational definition was selected based on clinical practice considerations and data availability in a real-world setting. Several limitations of this study should be acknowledged. First, residual confounding cannot be fully excluded despite the use of propensity score matching. Second, cognitive function was assessed at a single time point using the MoCA, which precludes evaluation of longitudinal changes and may limit precision in domain-specific cognitive assessment. Third, potentially relevant factors such as illness duration, episode status, and concomitant medications were not formally analyzed, and the relatively high proportion of long-term BDZ use was identified as an exploratory observation. Finally, the cognitive effects of short-term BDZs use were not evaluated in the present study. Future studies using multicenter, longitudinal designs and controlled interventional approaches are needed to further characterize the clinical factors associated with the relationship between BDZs use and cognitive function. The findings of the present study may have clinical implications for the use of BDZs in patients with schizophrenia. Clinicians may consider paying attention to treatment duration and cognitive status during BDZ therapy, while carefully weighing potential anxiolytic or sedative benefits against possible associations with cognitive impairment. Decisions regarding dose reduction, discontinuation, or the use of alternative interventions should be individualized and supported by further empirical evidence. Conclusions Long-term use of BDZs was associated with lower global cognitive performance in patients with schizophrenia receiving atypical antipsychotics, with pronounced deficits in visuospatial/executive function, naming, language, and abstraction. Long-term BDZs use was independently associated with cognitive impairment, whereas years of education was associated with cognitive impairment. These findings underscore the importance of monitoring cognitive function in patients with schizophrenia treated with BDZs. Abbreviations BDZs benzodiazepines E/I excitation-inhibition GABA gamma-aminobutyric acid AAP atypical antipsychotic MoCA the Montreal Cognitive Assessment PANSS the Positive and Negative Syndrome Scale CGI-S the Clinical Global Impression-Severity Scale PSP the Personal and Social Performance Scale PSM propensity score matching SD standard deviation OR odds ratio 95% CI 95% confidence interval Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of the Shanghai Mental Health Center (2010-35). All participants provided written informed consent. Consent for publication Not applicable. Declaration of competing interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Fundings The work was supported by Collaborative Innovation Center for Clinical and Translational Science by Ministry of Education & Shanghai (CCTS-202306); Shanghai Clinical Research Center for Mental Health (19MC1911100). The funders had no role in the design, data collection, analysis, interpretation, or writing of this study. Author Contribution Caiping Liu: Conceptualization, Formal analysis, Writing – original draft. Lei Zhang: Investigation, Methodology, Data curation. Qiyang Pan: Investigation, Formal analysis. Yue Shi: Data curation, Visualization. Wenjuan Yu:Investigation, Writing – review ; editing. Guanjun Li:Methodology. Writing – review ; editing. Huafang Li:Writing – original draft, Writing – review ; editing, supervision, Funding acquisition. Acknowledgements: We are grateful to all the psychiatrists and subjects who participated in this study. 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Is Long-Term Benzodiazepine Use a Risk Factor for Cognitive Decline? Results of a Systematic Review. J Addict. 2020;2020:1569456. Yu W, Huang J, He S, Zhang L, Shen Y, Li H. Safety and related factors of treatment with long-term atypical antipsychotic in Chinese patients with schizophrenia: observational study. Gen Psychiatr. 2021;34(1):e100289. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76. Tianmei S, Liang S, Yun'ai S, Chenghua T, Jun Y, Jia C, et al. The Chinese version of the Personal and Social Performance Scale (PSP): validity and reliability. Psychiatry Res. 2011;185(1–2):275–9. Gay W. Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology (revised). Rockville MD:• National Institute of Mental Health—1976; 1976. Wu C, Dagg P, Molgat C. A pilot study to measure cognitive impairment in patients with severe schizophrenia with the Montreal Cognitive Assessment (MoCA). Schizophr Res. 2014;158(1–3):151–5. Hashimoto Y, Yasunaga H. Theory and practice of propensity score analysis. Annals Clin Epidemiol. 2022;4(4):101–9. Sundermann EE, Saloner R, Rubtsova A, Nguyen AL, Letendre S, Moore RC, et al. The association between benzodiazepine use and greater risk of neurocognitive impairment is moderated by medical burden in people with HIV. J Neurovirol. 2022;28(3):410–21. Savić B, Jerotić S, Ristić I, Zebić M, Jovanović N, Russo M, et al. Long-Term Benzodiazepine Prescription During Maintenance Therapy of Individuals With Psychosis Spectrum Disorders—Associations With Cognition and Global Functioning. Clin Neuropharmacol. 2021;44(3):89–93. Baandrup L, Fagerlund B, Glenthoj B. Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder: a randomized clinical trial of add-on melatonin versus placebo. Eur Arch Psychiatry Clin Neurosci. 2017;267(2):163–71. Stern Y. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol. 2012;11(11):1006–12. Brunette MF, Noordsy DL, Xie H, Drake RE. Benzodiazepine use and abuse among patients with severe mental illness and co-occurring substance use disorders. Psychiatric Serv. 2003;54(10):1395–401. Rosenqvist TW, Wium-Andersen MK, Wium-Andersen IK, Jørgensen MB, Osler M. Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation. Am J Psychiatry. 2024;181(3):246–54. Kurko TA, Saastamoinen LK, Tähkäpää S, Tuulio-Henriksson A, Taiminen T, Tiihonen J, et al. Long-term use of benzodiazepines: Definitions, prevalence and usage patterns - a systematic review of register-based studies. Eur Psychiatry. 2015;30(8):1037–47. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 24 Mar, 2026 Reviews received at journal 23 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviews received at journal 04 Mar, 2026 Reviewers agreed at journal 26 Feb, 2026 Reviewers agreed at journal 26 Feb, 2026 Reviewers invited by journal 26 Feb, 2026 Editor assigned by journal 26 Feb, 2026 Editor invited by journal 16 Feb, 2026 Submission checks completed at journal 16 Feb, 2026 First submitted to journal 16 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-8797752","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":600125356,"identity":"f983aa5a-4d86-47e6-92f7-c19663b94226","order_by":0,"name":"Caiping Liu","email":"","orcid":"","institution":"Shanghai Mental Health Center","correspondingAuthor":false,"prefix":"","firstName":"Caiping","middleName":"","lastName":"Liu","suffix":""},{"id":600125358,"identity":"0832ff3f-e0b0-4e90-9833-af285980f793","order_by":1,"name":"Lei Zhang","email":"","orcid":"","institution":"Shanghai Mental Health Center","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Zhang","suffix":""},{"id":600125359,"identity":"e9c3464d-9234-41dc-885d-ee289ce6ae32","order_by":2,"name":"Qiyang Pan","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Qiyang","middleName":"","lastName":"Pan","suffix":""},{"id":600125360,"identity":"b73bb2e7-1858-4a95-9e81-c8f6fef7146a","order_by":3,"name":"Yue Shi","email":"","orcid":"","institution":"Shanghai Mental Health Center","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Shi","suffix":""},{"id":600125361,"identity":"7dccee61-d40d-45af-8658-b1d803ee81fe","order_by":4,"name":"Wenjuan Yu","email":"","orcid":"","institution":"Shanghai Mental Health Center","correspondingAuthor":false,"prefix":"","firstName":"Wenjuan","middleName":"","lastName":"Yu","suffix":""},{"id":600125362,"identity":"95caa02f-98db-4b2e-bbb4-6cc3dcdda662","order_by":5,"name":"Guanjun Li","email":"","orcid":"","institution":"Shanghai Mental Health Center","correspondingAuthor":false,"prefix":"","firstName":"Guanjun","middleName":"","lastName":"Li","suffix":""},{"id":600125364,"identity":"56b1055c-bc76-46b2-b501-80a3522a31d3","order_by":6,"name":"Huafang Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYBACPmYeIGkDxOwNDMxEaWEDa0kDYp4DxGphgGmRSCBWCzvvMYkfCXZ58pHPn24uqGGQM+9fwPi5AK/D+NIkexKSiw1v55jdnnGMwVjmxgNm6Rn4/WImwfuDOXHj7By227wNDIkzJA5APIhPi+SfhPrEjTOPPyNeizRPwuHE+RIMZhAt/A0EtRhbyyQcT9zAA/QLzzEJYwkJxmZpfFr4+c8Y3nyTUJ04vx3oMJ4aGzkJ/sMHP+PTAgcGB8CUBBAlNhCjgYFBHq6O/wBxOkbBKBgFo2DEAAA2f0Cm7V6CdQAAAABJRU5ErkJggg==","orcid":"","institution":"Shanghai Mental Health Center","correspondingAuthor":true,"prefix":"","firstName":"Huafang","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2026-02-05 13:40:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8797752/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8797752/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104171741,"identity":"3ab42f5c-b17b-419c-ac6a-5c4f99f9762f","added_by":"auto","created_at":"2026-03-08 14:55:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":116449,"visible":true,"origin":"","legend":"\u003cp\u003eTrial profile.\u003c/p\u003e\n\u003cp\u003eNote: BDZs: benzodiazepines; PSM: propensity score matching; MoCA: Montreal Cognitive Assessment.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8797752/v1/e4a15e8ee0e063e8899bc050.jpg"},{"id":104171795,"identity":"c0398e3d-3bac-4f01-8445-7f2a0e85e15c","added_by":"auto","created_at":"2026-03-08 14:55:32","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":80069,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelates of cognitive impairment\u003c/p\u003e\n\u003cp\u003eNote: BDZs: benzodiazepines; OR: odds ratio.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8797752/v1/a1e3caa0518ff3cdbe5b2aee.jpg"},{"id":104404680,"identity":"998b97b8-31a2-419c-9522-f01707abe646","added_by":"auto","created_at":"2026-03-11 12:20:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1098656,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8797752/v1/54a42b8b-2f41-462a-9e58-094f41574f10.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term benzodiazepine use is associated with poorer cognitive function in schizophrenia: Findings from the SALT-C cohort","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCognitive impairment is recognized as a core feature of schizophrenia, including deficits in working memory, executive function, attention, and processing speed, affecting approximately 75\u0026ndash;80% of patients to varying degrees [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Given that these deficits are linked to impaired social functioning in domains such as community integration, occupational competence, and daily skill acquisition, cognitive dysfunction has been widely recognized as a major determinant of long-term outcome in schizophrenia [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe pathogenesis of cognitive impairment is complex. Current evidence implicates a combination of genetic vulnerability, cortical excitation-inhibition (E/I) imbalance, and dysregulation of neurotransmitters involving dopamine, glutamate, and gamma-aminobutyric acid (GABA) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Several studies have indicated that pharmacological treatment also plays a crucial role in the progression of cognitive impairment observed in schizophrenia [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Given the role of GABAergic dysfunction in cognitive processes, medications targeting the GABA system, particularly benzodiazepines (BDZs), may have clinically relevant effects on cognition in schizophrenia.\u003c/p\u003e \u003cp\u003eThe cognitive benefits of currently available psychotropic medications are limited [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, some treatments, such as conventional antipsychotics, may worsen cognitive impairment in schizophrenia [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Meanwhile, there is growing concern about the effects of BDZs on cognitive function in schizophrenia. BDZs represent one of the most frequently used adjunctive pharmacotherapies in patients with schizophrenia, and are widely used for various therapeutic purposes, including the management of anxiety and sleep disturbances, the mitigation of antipsychotic side effects, and rapid tranquilization [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the CATIE trial, the co-prescription rate of BDZs was approximately 22%. Notably, another study demonstrated that once initiated, long-term use was highly prevalent, with cumulative treatment duration exceeding one year in up to 62.9% of schizophrenia patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough BDZs are considered safe and effective for short-term use, their potential for long-term cognitive impact remains a concern. In non-psychotic patients, long-term BDZs use is often associated with broad cognitive deficits [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A recent meta-analysis has confirmed this association, although the severity of impairment and the specific cognitive domains involved vary considerably [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The underlying mechanisms for BDZ‑induced cognitive impairment may involve the acute enhancement of GABA\u003csub\u003eA\u003c/sub\u003e receptor-mediated inhibitory neurotransmission [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This disruption of hippocampal and prefrontal cortical function can lead to deficits in working memory, executive function, and attention. Additionally, long‑term BDZs use may promote neuroplastic changes or receptor downregulation, further exacerbating cognitive decline [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, it remains uncertain whether these mechanisms operate similarly in schizophrenia, given baseline cognitive impairment and altered GABAergic signaling.\u003c/p\u003e \u003cp\u003eThe cognitive effects of BDZs in schizophrenia remain debated. A cross-sectional study reported an association between BDZs use and poorer cognitive and social function in older adults (\u0026ge;\u0026thinsp;55 years) with schizophrenia, along with increased hospitalization duration and readmission rates [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Research on community-dwelling stabilized patients has shown that daily use of BDZs is associated with reduced working memory and attentional performance [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In contrast, a few studies have found no significant association between benzodiazepine use and cognitive function [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Moreover, research suggests that cognitive deficits associated with BDZs may be at least partially reversible. In a Japanese cohort of patients with schizophrenia, significant improvement in verbal memory was observed following gradual BDZs discontinuation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Longitudinal studies have not consistently demonstrated progressive decline over time; some evidence suggests that cognitive deficits appear to stabilize after a certain duration of exposure [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These conflicting findings may be attributed to variations in study design, BDZs dosage, exposure duration, or the cognitive domains assessed. Thus, the real-world association between long-term BDZs use and cognitive function in schizophrenia has yet to be clearly characterized.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to examine the association between long-term BDZs use and cognitive function in patients with schizophrenia using real-world data. Propensity score matching was applied to balance key clinical characteristics, allowing for a more robust assessment of the cognitive impact of long-term BDZs use in routine clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThe data for this study were obtained from the SALT-C study, an observational study on safety and related factors of treatment with atypical antipsychotics in Chinese patients with schizophrenia [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Participants were recruited from the Shanghai Mental Health Center between 2016 and 2019. All participants were outpatients or inpatients aged 18 years or older with a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), confirmed independently by at least two attending psychiatrists. All participants were either receiving or planning to initiate atypical antipsychotic (AAP) treatment. The study protocol was approved by the Ethics Committee of the Shanghai Mental Health Center (2010-35).\u003c/p\u003e \u003cp\u003eBased on this cohort, this analysis aimed to evaluate the association between long-term BDZs use and cognitive function. Participants were eligible for the long-term BDZs user group if they had been using BDZs at a stable dosage for at least 60 consecutive days prior to enrollment. Participants were eligible for the BDZs non-user group if they had no prior history of BDZs use.\u003c/p\u003e \u003cp\u003ePatients were excluded if they had comorbid psychiatric disorders (including bipolar disorder, major depressive disorder, or substance-induced psychotic disorders); neurological diseases (such as epilepsy, Parkinson\u0026rsquo;s disease, stroke, or traumatic brain injury); severe physical illnesses; a history of substance abuse or dependence (except nicotine) within the preceding three months; intellectual disability or severe cognitive impairment that would preclude completion of cognitive assessments; refusal or inability to provide informed consent; concurrent participation in another clinical study; were deemed unsuitable by the investigator; were currently receiving electroconvulsive therapy (ECT) or modified ECT without convulsion; or were currently using nootropics or potent anticholinergic agents.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003eDemographic and clinical data were collected, including age, gender, years of education, episode and duration of illness. Detailed medication information was recorded for all prescribed AAPs, and for concomitant medications such as antidepressants. Information on BDZs was recorded, including the specific type, initial prescription date, and duration of use. Long-term use was defined as continuous use exceeding 60 days.\u003c/p\u003e \u003cp\u003eCognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The MoCA assesses multiple cognitive domains, including attention and concentration, executive function, memory, language, visuospatial ability, abstract thinking, and orientation. The total score ranges from 0 to 30, with higher scores indicating better cognitive performance; a cutoff score of 26 was used, with scores\u0026thinsp;\u0026ge;\u0026thinsp;26 indicating no cognitive impairment and scores\u0026thinsp;\u0026lt;\u0026thinsp;26 indicating cognitive impairment.\u003c/p\u003e \u003cp\u003ePsychopathology was assessed using the total score and the positive, negative, and general psychopathology subscale scores of the Positive and Negative Syndrome Scale (PANSS) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Illness severity and psychosocial functioning were evaluated using the Clinical Global Impression-Severity (CGI-S) scale and the Personal and Social Performance (PSP) scale [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll psychological assessments were conducted by trained psychiatrists, having completed standardized training for each scale and demonstrated inter-rater reliability prior to data collection.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePropensity score matching (PSM) was performed to reduce selection bias between the study groups. A 1:1 matching protocol was applied based on age, gender, illness duration, and type of AAPs.\u003c/p\u003e \u003cp\u003eAll statistical analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables following normal distribution were expressed as mean and standard deviation [M (SD)]; non-normally distributed data were expressed as median and interquartile range [M (P25, P75)]. Categorical and ordinal variables were summarized as frequencies and percentages. Between-group comparisons were performed using independent-samples t-tests or Mann\u0026ndash;Whitney U tests. Multivariate analysis was performed using binary logistic regression. A two-tailed P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDemographic characteristics and propensity score matching\u003c/h2\u003e \u003cp\u003eOf 842 patients initially screened, 690 were included in the analysis, comprising 62 long-term BDZs users and 628 non-users (Fig.\u0026nbsp;1). Among patients treated with BDZs, 66.0% were long-term users. The most commonly prescribed BDZs were alprazolam, followed by clonazepam and lorazepam; other agents included oxazepam, estazolam, and diazepam.\u003c/p\u003e \u003cp\u003eBefore propensity score matching, significant differences were observed between the two groups in age, episode status (first episode vs. relapse), illness duration, and type of AAPs prescribed (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eAfter propensity score matching, 57 patients were retained in the long-term BDZs user group and the BDZs non-user group, respectively. There were no significant differences between the two groups in age, gender, years of education, patient type (outpatient vs. inpatient), schizophrenia subtype, episode status, illness duration, or type of AAPs (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), indicating adequate covariate balance. In the long-term BDZs user group, the commonly prescribed AAP was olanzapine (43.9%), followed by aripiprazole (17.5%). Similarly, in the BDZs non-user group, olanzapine was the most commonly prescribed AAP (45.6%), followed by aripiprazole (17.5%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 1\u003c/b\u003e Trial profile.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNote\u003c/strong\u003e \u003cp\u003eBDZs: benzodiazepines; PSM: propensity score matching; MoCA: Montreal Cognitive Assessment.\u003c/p\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\u003eDemographic characteristics.\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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\u003eBefore PSM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eAfter PSM\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLong-term BDZs users\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBDZs non-users\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eZ/χ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLong-term BDZs users\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBDZs non-users\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eZ/χ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;628)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.00(46.75,63.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.00(37.00,60.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.897\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57.00(49.00,64.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e57.00(48.00,63.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.889\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.208\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=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.843\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (64.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e353 (56.2%)\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 \u003cp\u003e37(64.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38(66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (35.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e275 (43.8%)\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 \u003cp\u003e20(35.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e19(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYears of education\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.00(8.00,12.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.00(9.00,12.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.00(8.00,12.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.00(8.00,12.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.703\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.449\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.066\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=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.309\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutpatient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84 (13.4%)\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 \u003cp\u003e1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInpatient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (96.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e544 (86.6%)\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 \u003cp\u003e56 (98.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e54 (94.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchizophrenia subtype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.877\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.096\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=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.718\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHebephrenic schizophrenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (0.9%)\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 \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCatatonic schizophrenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (0.9%)\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 \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParanoid schizophrenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e227 (36.1%)\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 \u003cp\u003e18 (31.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20 (35.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUndifferentiated schizophrenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (6.8%)\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 \u003cp\u003e10 (17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8 (14.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResidual schizophrenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (51.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e346 (55.1%)\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 \u003cp\u003e29 (50.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29 (50.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpisode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\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=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.142\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-episode status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108 (17.2%)\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 \u003cp\u003e2 (3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (96.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e520 (82.8%)\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 \u003cp\u003e55 (96.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e51 (89.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIllness duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.00(18.50,35.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.50(10.00,30.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.00(19.00,37.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28.00(17.00,35.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.691\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.758\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003csup\u003e*\u003c/sup\u003e\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=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuetiapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (5.9%)\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 \u003cp\u003e1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlanzapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e180 (28.7%)\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 \u003cp\u003e25 (43.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26 (45.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisperidone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (14.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143 (22.8%)\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 \u003cp\u003e9 (15.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9 (15.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAripiprazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122 (19.4%)\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 \u003cp\u003e10 (17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10 (17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZiprasidone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (1.3%)\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 \u003cp\u003e2 (3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaliperidone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (2.2%)\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 \u003cp\u003e3 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmisulpride\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (4.8%)\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 \u003cp\u003e1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerospirone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\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 \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClozapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (12.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (15.0%)\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 \u003cp\u003e6 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBDZ Treatment duration\u003c/p\u003e \u003cp\u003e(months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.00(10.70,48.00)\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 \u003cp\u003e31.00(14.50,50.00)\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 \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eNote: Data are presented as number (percentage%) or median (interquartile range). PSM: propensity score matching; BDZs: benzodiazepines; AAP: atypical antipsychotic. \u003cem\u003e* P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComparison of clinical symptoms and severity between groups\u003c/h2\u003e \u003cp\u003eThe total PANSS score was 57.50 (49.00, 75.75) in the long-term BDZs user group and 55.00 (46.75, 70.25) in the BDZs non-user group, with no significant difference observed between the groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Similarly, no significant differences were observed between the groups in the PANSS positive, negative, or general psychopathology subscales (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The CGI-S and PSP scores also showed no significant differences between groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), indicating comparable severity of clinical symptoms and social functioning (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\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\u003eComparison of clinical symptoms, severity, and social performance.\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=\".\" 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=\"char\" char=\".\" 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\u003eLong-term BDZs users\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBDZs non-users\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eZ\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\u003ePANSS total score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e57.50 (49.00,75.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55.00 (46.75,70.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS-positive score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.00 (7.00,16.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.50 (7.00,12.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.814\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.415\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS-negative score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.00 (16.25,25.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20.00 (15.75,24.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.610\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS-general psychopathology score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28.00 (24.00,36.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27.00 (22.00,35.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.832\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.405\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCGI-S score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.00 (3.00,4.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.00 (3.00,4.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60.00 (40.00,70.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60.00(45.00,65.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.216\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.829\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: Data are presented as median (interquartile range). BDZs: benzodiazepines; PANSS: Positive and Negative Syndrome Scale; CGI-S: Clinical Global Impression-Severity Scale; PSP: Personal and Social Performance Scale.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eComparison of cognitive function between groups\u003c/h3\u003e\n\u003cp\u003eThe mean total MoCA score was significantly lower in the long-term BDZs user group [16.02 (6.69)] compared with the BDZs non-user group [19.33 (7.11); P\u0026thinsp;=\u0026thinsp;0.012, t\u0026thinsp;=\u0026thinsp;2.566]. Both groups scored below the cutoff of 26, indicating the presence of overall cognitive impairment.\u003c/p\u003e \u003cp\u003eAnalysis of MoCA subdomains showed significantly poorer performance in the long-term BDZs user group compared with the BDZs non-user group on visuospatial/executive function (P\u0026thinsp;=\u0026thinsp;0.012, Z = -2.501), naming (P\u0026thinsp;=\u0026thinsp;0.025, Z = -2.236), language (P\u0026thinsp;=\u0026thinsp;0.032, Z = -2.139), and abstraction (P\u0026thinsp;=\u0026thinsp;0.032, Z = -2.142). No significant differences were observed in attention, delayed recall, or orientation (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\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 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of cognitive function.\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=\".\" 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=\"char\" char=\".\" 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\u003eLong-term BDZs users\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBDZs non-users\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et/Z\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\u003eMoCA total score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16.02 (6.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19.33 (7.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.566\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisuospatial/executive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.00 (1.00,3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.00 (1.50,4.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.501\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNaming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.00 (2.00,3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.00 (2.00,3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.025\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAttention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.00 (3.00,5.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.00 (3.00,6,00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.891\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLanguage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.00 (0.00,1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.00 (0.00,2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.032\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbstraction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.82 (0.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.18 (0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.032\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelayed recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00 (0.00,2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.00 (0.00,2.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.856\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrientation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.00 (4.00,6.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.00 (5.00,6.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.547\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.122\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: Data are presented as mean (SD) or median (interquartile range). BDZs: benzodiazepines; MoCA: Montreal Cognitive Assessment. \u003cem\u003e* P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eMultivariate Regression Analysis on correlates of cognitive impairment\u003c/h3\u003e\n\u003cp\u003eA binary logistic regression model was constructed to assess factors associated with cognitive impairment. Normal cognition (MoCA\u0026thinsp;\u0026ge;\u0026thinsp;26) served as the reference category for the dependent variable. The model included the following independent variables: age, gender, years of education, illness duration, and long-term BDZs use, and showed good model fit (χ\u0026sup2; = 3.088, P\u0026thinsp;=\u0026thinsp;0.929).\u003c/p\u003e \u003cp\u003eAmong these variables, long-term BDZs use was independently associated with cognitive impairment (OR\u0026thinsp;=\u0026thinsp;7.728, P\u0026thinsp;=\u0026thinsp;0.017), whereas years of education was associated with cognitive impairment (OR\u0026thinsp;=\u0026thinsp;0.740, P\u0026thinsp;=\u0026thinsp;0.007), while age, gender, and duration of illness were not significantly associated with cognitive impairment (Fig.\u0026nbsp;2, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 2\u003c/b\u003e Correlates of cognitive impairment\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNote\u003c/strong\u003e \u003cp\u003eBDZs: benzodiazepines; OR: odds ratio.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLogistic Regression analysis of factors associated with cognitive function\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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 \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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWald χ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong-term BDZs use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7.728\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e41.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYears of education\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.355\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.007\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.595\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.920\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.986\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.920\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.794\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.522\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.663\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.351\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.892\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIllness duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.978\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.150\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eNote: \u003cem\u003e* P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis real-world study explored the association between long-term BDZs use and cognitive function in patients with schizophrenia. The primary finding was that patients with long-term BDZs use demonstrated significantly poorer overall cognitive performance than BDZs non-users. Moreover, long-term BDZs use was independently associated with cognitive impairment, while years of education was negatively associated with cognitive impairment. Additionally, it was observed that the proportion of long-term users among BDZ users was relatively high.\u003c/p\u003e \u003cp\u003eIn this study, cognitive function was assessed using the MoCA, a widely used and sensitive screening tool for cognitive impairment that has been validated for detecting cognitive deficits in patients with schizophrenia [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Propensity score matching was applied to balance baseline characteristics and account for potential confounding factors between long-term BDZs users and non-users [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Patients with long-term BDZs use had lower total MoCA scores, with more pronounced deficits observed in naming, language, abstraction, and visuospatial/executive subdomains compared with non-users, indicating an association between long-term BDZs use and poorer performance in these cognitive domains. Similar associations have also been reported in the non-psychiatric population [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This finding aligns with the multicenter FACE-SZ study, which reported that among 407 clinically stable patients with schizophrenia, long-term BDZs use was significantly associated with impairments in verbal memory and working memory [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similarly, previous research has reported lower scores on the Global Assessment of Functioning\u0026ndash;Cognition in Schizophrenia (GAF-CogS) scale in patients with schizophrenia spectrum disorders receiving long-term BDZ therapy[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Despite methodological differences, impairments across multiple cognitive domains were identified, particularly in language and executive function. Moreover, the present study found that patients with long-term BDZs use performed worse in visuospatial and abstraction domains, which is consistent with previous findings [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Overall, these observations suggest an association between long-term BDZs use and deficits across multiple cognitive domains in patients with schizophrenia.\u003c/p\u003e \u003cp\u003eAlthough some studies have suggested that long-term BDZs users present with more severe clinical symptoms [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], no significant between-group differences in clinical symptom severity or social functioning were observed in our sample.\u003c/p\u003e \u003cp\u003eIn the present study, multivariable logistic regression analysis indicated that long-term BDZs use was positively associated with cognitive impairment in patients with schizophrenia, whereas years of education were inversely associated with cognitive impairment. These findings further suggest long-term BDZs use independently associated with an increased cognitive impairment after adjustment for relevant covariates. Nevertheless, although long-term benzodiazepine use was associated with greater cognitive impairment (OR\u0026thinsp;=\u0026thinsp;7.728), the relatively wide confidence interval indicates limited precision of the effect estimate. The limited sample size and heterogeneity in duration of BDZs use may contribute to this uncertainty. These results point to a possible risk trend, with the clinical significance requiring further investigation in larger, prospective studies. The association between years of education and cognitive impairment is consistent with the cognitive reserve hypothesis, whereby educational attainment could increase the tolerance to disease-related brain dysfunction [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong all initially recruited patients prescribed BDZs, approximately two-thirds were identified as long-term users. The mean duration of BDZs use was 31 months, exceeding two years. Although the overall rate of BDZs co-prescription in the baseline dataset was lower than that reported in some previous studies, the proportion of long-term users was relatively high. This observation might be partially attributable to real-world prescribing practices, as suggested in previous study, whereby BDZ treatment, once initiated, tends to be maintained over extended periods in certain clinical settings [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Similar findings have been reported, with up to 62.9% of patients with schizophrenia exposed to BDZs for more than one year [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. This interpretation remains uncertain and needs to be evaluated in longitudinal studies focusing on long-term BDZs prescribing practices and related clinical factors.\u003c/p\u003e \u003cp\u003eDefinitions of \u003cem\u003elong-term use\u003c/em\u003e vary across studies, ranging from several months to years; the most common thresholds are continuous use for 3\u0026ndash;12 months [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In the present study, long-term use was defined as continuous exposure for more than two months. This operational definition was selected based on clinical practice considerations and data availability in a real-world setting.\u003c/p\u003e \u003cp\u003eSeveral limitations of this study should be acknowledged. First, residual confounding cannot be fully excluded despite the use of propensity score matching. Second, cognitive function was assessed at a single time point using the MoCA, which precludes evaluation of longitudinal changes and may limit precision in domain-specific cognitive assessment. Third, potentially relevant factors such as illness duration, episode status, and concomitant medications were not formally analyzed, and the relatively high proportion of long-term BDZ use was identified as an exploratory observation. Finally, the cognitive effects of short-term BDZs use were not evaluated in the present study. Future studies using multicenter, longitudinal designs and controlled interventional approaches are needed to further characterize the clinical factors associated with the relationship between BDZs use and cognitive function.\u003c/p\u003e \u003cp\u003eThe findings of the present study may have clinical implications for the use of BDZs in patients with schizophrenia. Clinicians may consider paying attention to treatment duration and cognitive status during BDZ therapy, while carefully weighing potential anxiolytic or sedative benefits against possible associations with cognitive impairment. Decisions regarding dose reduction, discontinuation, or the use of alternative interventions should be individualized and supported by further empirical evidence.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eLong-term use of BDZs was associated with lower global cognitive performance in patients with schizophrenia receiving atypical antipsychotics, with pronounced deficits in visuospatial/executive function, naming, language, and abstraction. Long-term BDZs use was independently associated with cognitive impairment, whereas years of education was associated with cognitive impairment. These findings underscore the importance of monitoring cognitive function in patients with schizophrenia treated with BDZs.\u003c/p\u003e"},{"header":"Abbreviations","content":" \u003cp\u003eBDZs benzodiazepines\u003c/p\u003e \u003cp\u003eE/I excitation-inhibition\u003c/p\u003e \u003cp\u003eGABA gamma-aminobutyric acid\u003c/p\u003e \u003cp\u003eAAP atypical antipsychotic\u003c/p\u003e \u003cp\u003eMoCA the Montreal Cognitive Assessment\u003c/p\u003e \u003cp\u003ePANSS the Positive and Negative Syndrome Scale\u003c/p\u003e \u003cp\u003eCGI-S the Clinical Global Impression-Severity Scale\u003c/p\u003e \u003cp\u003ePSP the Personal and Social Performance Scale\u003c/p\u003e \u003cp\u003ePSM propensity score matching\u003c/p\u003e \u003cp\u003eSD standard deviation\u003c/p\u003e \u003cp\u003eOR odds ratio\u003c/p\u003e \u003cp\u003e95% CI 95% confidence interval\u003c/p\u003e \u003c/p\u003e\u003cp\u003e "},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e \u003cp\u003e The study was approved by the Ethics Committee of the Shanghai Mental Health Center (2010-35). All participants provided written informed consent.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eDeclaration of competing interest:\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFundings\u003c/h2\u003e \u003cp\u003eThe work was supported by Collaborative Innovation Center for Clinical and Translational Science by Ministry of Education \u0026amp; Shanghai (CCTS-202306); Shanghai Clinical Research Center for Mental Health (19MC1911100). The funders had no role in the design, data collection, analysis, interpretation, or writing of this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eCaiping Liu: Conceptualization, Formal analysis, Writing \u0026ndash; original draft. Lei Zhang: Investigation, Methodology, Data curation. Qiyang Pan: Investigation, Formal analysis. Yue Shi: Data curation, Visualization. Wenjuan Yu:Investigation, Writing \u0026ndash; review ; editing. Guanjun Li:Methodology. Writing \u0026ndash; review ; editing. Huafang Li:Writing \u0026ndash; original draft, Writing \u0026ndash; review ; editing, supervision, Funding acquisition.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eWe are grateful to all the psychiatrists and subjects who participated in this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analysed during the current study are not publicly available due to the ethical and institutional restrictions. The informed consent and ethics approval did not include public data sharing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMcCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-An Overview. JAMA Psychiatry. 2020;77(2):201\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, et al. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018;44(6):1195\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarvey PD, Bosia M, Cavallaro R, Howes OD, Kahn RS, Leucht S, et al. Cognitive dysfunction in schizophrenia: An expert group paper on the current state of the art. Schizophr Res Cogn. 2022;29:100249.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDickinson D, Ramsey ME, Gold JM. Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatry. 2007;64(5):532\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajji TK, Miranda D, Mulsant BH. Cognition, function, and disability in patients with schizophrenia: a review of longitudinal studies. Can J Psychiatry. 2014;59(1):13\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJavitt DC. Cognitive impairment associated with schizophrenia: from pathophysiology to treatment. Annu Rev Pharmacol Toxicol. 2023;63(1):119\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012(213):11\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiddle PF. Cognitive impairment in schizophrenia: its impact on social functioning. Acta Psychiatr Scand Suppl. 2000;400:11\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcEvoy JP. The costs of schizophrenia. J Clin Psychiatry. 2007;68(Suppl):4\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCutcheon RA, Keefe RS, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28(5):1902\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShimada T, Kobayashi G, Saeki Y, Mizukoshi C, Chikazawa K, Nokura K, et al. A Retrospective Study on the Relationship Between Cognitive Function and Social Function in Patients With Schizophrenia. J Clin Med Res. 2022;14(9):348\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHalverson TF, Orleans-Pobee M, Merritt C, Sheeran P, Fett AK, Penn DL. Pathways to functional outcomes in schizophrenia spectrum disorders: Meta-analysis of social cognitive and neurocognitive predictors. Neurosci Biobehav Rev. 2019;105:212\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaar SJ, Natesan S, McCutcheon R, Howes OD. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 2020;172:107704.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoncrieff J, Cohen D, Mason JP. The subjective experience of taking antipsychotic medication: a content analysis of Internet data. Acta Psychiatr Scand. 2009;120(2):102\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClark RE, Xie H, Brunette MF. Benzodiazepine prescription practices and substance abuse in persons with severe mental illness. J Clin Psychiatry. 2004;65(2):151\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu CS, Lin YJ, Liu SK. Benzodiazepine use among patients with schizophrenia in Taiwan: a nationwide population-based survey. Psychiatr Serv. 2011;62(8):908\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarker MJ, Greenwood KM, Jackson M, Crowe SF. Cognitive effects of long-term benzodiazepine use: a meta-analysis. 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Neurobiol Dis. 2023;185:106248.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchuster JP, Hoertel N, von Gunten A, Seigneurie AS, Limosin F. Benzodiazepine use among older adults with schizophrenia spectrum disorder: prevalence and associated factors in a multicenter study. Int Psychogeriatr. 2020;32(4):441\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFond G, Berna F, Boyer L, Godin O, Brunel L, Andrianarisoa M, et al. Benzodiazepine long-term administration is associated with impaired attention/working memory in schizophrenia: results from the national multicentre FACE-SZ data set. Eur Arch Psychiatry Clin Neurosci. 2018;268(1):17\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHulkko AP, Murray GK, Moilanen J, Haapea M, Rannikko I, Jones PB, et al. Lifetime use of psychiatric medications and cognition at 43years of age in schizophrenia in the Northern Finland Birth Cohort 1966. 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J Neurovirol. 2022;28(3):410\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSavić B, Jerotić S, Ristić I, Zebić M, Jovanović N, Russo M, et al. Long-Term Benzodiazepine Prescription During Maintenance Therapy of Individuals With Psychosis Spectrum Disorders\u0026mdash;Associations With Cognition and Global Functioning. Clin Neuropharmacol. 2021;44(3):89\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaandrup L, Fagerlund B, Glenthoj B. Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder: a randomized clinical trial of add-on melatonin versus placebo. Eur Arch Psychiatry Clin Neurosci. 2017;267(2):163\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStern Y. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol. 2012;11(11):1006\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrunette MF, Noordsy DL, Xie H, Drake RE. Benzodiazepine use and abuse among patients with severe mental illness and co-occurring substance use disorders. Psychiatric Serv. 2003;54(10):1395\u0026ndash;401.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenqvist TW, Wium-Andersen MK, Wium-Andersen IK, J\u0026oslash;rgensen MB, Osler M. Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation. Am J Psychiatry. 2024;181(3):246\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKurko TA, Saastamoinen LK, T\u0026auml;hk\u0026auml;p\u0026auml;\u0026auml; S, Tuulio-Henriksson A, Taiminen T, Tiihonen J, et al. Long-term use of benzodiazepines: Definitions, prevalence and usage patterns - a systematic review of register-based studies. Eur Psychiatry. 2015;30(8):1037\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\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":"Benzodiazepines, schizophrenia, long-term use, cognitive function, atypical antipsychotics","lastPublishedDoi":"10.21203/rs.3.rs-8797752/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8797752/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe association between long-term use of benzodiazepines (BDZs) and cognitive function in patients with schizophrenia has not been fully characterized. This study aimed to investigate the relationship between long-term BDZs use and cognitive impairment in schizophrenia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData were derived from an observational study of treatment with atypical antipsychotics in Chinese patients with schizophrenia (SALT-C). Fifty-seven patients with long-term use of BDZs (\u0026ge;\u0026thinsp;60 days) were included, and 57 BDZs non-users were matched using propensity scores for age, sex, disease duration, and atypical antipsychotics received. Cognitive impairment was assessed using the Montreal Cognitive Assessment (MoCA); psychotic symptoms, illness severity, and psychosocial functioning were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale. Between-group comparisons were performed using independent-samples t-tests or Mann\u0026ndash;Whitney U tests. Multivariate analysis was performed using binary logistic regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe long-term BDZs user group showed a significantly lower total MoCA score [16.02 (6.69)] than the BDZs non-user group [19.33 (7.11)] (P\u0026thinsp;=\u0026thinsp;0.012). No significant between-group differences were observed in total scores on the PANSS, CGI-S, or PSP (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Long-term BDZs use was independently associated with cognitive impairment (OR\u0026thinsp;=\u0026thinsp;7.728, P\u0026thinsp;=\u0026thinsp;0.017), whereas years of education was negatively associated with cognitive impairment (OR\u0026thinsp;=\u0026thinsp;0.740, P\u0026thinsp;=\u0026thinsp;0.007).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eLong-term BDZs use is associated with poorer cognitive performance in patients with schizophrenia, suggesting that cognitive function should be monitored during BDZs treatment in this population.\u003c/p\u003e","manuscriptTitle":"Long-term benzodiazepine use is associated with poorer cognitive function in schizophrenia: Findings from the SALT-C cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 14:55:11","doi":"10.21203/rs.3.rs-8797752/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-24T09:35:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T16:05:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286595606880757986838282236308618391373","date":"2026-03-05T16:52:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-04T05:04:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267502384642664578807783426198561126083","date":"2026-02-27T01:55:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"140333215217227311318085848983663920100","date":"2026-02-26T20:28:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-26T16:23:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-26T16:01:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-16T10:38:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-16T06:22:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2026-02-16T06:19:31+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":"6fdaca7a-ecc6-4623-a6f5-22133825dc56","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T10:09:52+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 14:55:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8797752","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8797752","identity":"rs-8797752","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}