The value of repetitive transcranial magnetic stimulation combined with amisulpride enhancement olanzapine therapy for resistant treatment-refractory schizophrenia

The value of repetitive transcranial magnetic stimulation combined with amisulpride enhancement olanzapine therapy for resistant treatment-refractory schizophrenia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The value of repetitive transcranial magnetic stimulation combined with amisulpride enhancement olanzapine therapy for resistant treatment-refractory schizophrenia Ou Yang, Liyan Yu, Yang Li, Miaozhen Zhou, Qianying Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7377896/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: Repetitive transcranial magnetic stimulation (rTMS) is a widely used enhancement therapy for schizophrenia, but there are few controlled studies on the combination of rTMS and amisulpride enhancement therapy. The aim of this study is to explore the value of rTMS combined with amisulpride enhanced olanzapine therapy for resistant treatment-refractory schizophrenia (TRS) patients. Methods: We conducted a retrospective analysis based on records of TRS patients who received amisulpride enhanced olanzapine treatment at the Third People's Hospital of Yongkang City from December 2022 to September 2023. Patients are divided into rTMS group and Non-rTMS group based on whether they receive combined rTMS treatment. We examined the patient's Positive and Negative Symptom Rating Scale (PANSS) scores, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores, World Health Organization Quality of Life Questionnaire (WHOQOL-BREF), and incidence of adverse events. Results: After treatment, the scores of PANNS in both groups significantly decreased, and the rTMS group was lower than the Non-rTMS group (P<0.05); The scores of RBANS and WHOQOL-BREF in both groups significantly increased (P<0.05); Except for the attention sub item, all other sub scores in the rTMS group were higher than those in the Non-rTMS group (P0.05). Conclusions: The combination of rTMS and amisulpride to enhance olanzapine treatment for TRS has high value. Core Tip: rTMS is a widely used treatment method for schizophrenia. This study found that rTMS combined with amisulpride enhanced olanzapine treatment for TRS can significantly improve patients' symptoms, cognitive function, and quality of life, with tolerability and safety. Repetitive transcranial magnetic stimulation amisulpride enhancement therapy olanzapine resistant treatment-refractory schizophrenia INTRODUCTION Schizophrenia is a serious mental disorder characterized by hallucinations, delusions, disordered thinking, emotional apathy, and decreased willpower. [1,2] At present, clozapine is the only evidence-based antipsychotic drug used to treat TRS patients and is widely used in the treatment of schizophrenia. [3] Clozapine can effectively block dopamine D2 receptors and 5-hydroxytryptamine (5-HT2A) receptors, thereby improving patients' symptoms. [3,4] However, there are still 30% -50% of patients whose symptoms have not been effectively improved after treatment with clozapine, and even have recurrent or worsening conditions. [3-6] For some patients, the use of clozapine has been excluded due to clinical contraindications, including discontinuation of clozapine due to adverse events. Therefore, alternative treatment is needed for those who do not want to start using clozapine due to concerns about side effects or the need for monitoring. [4-6] The effectiveness of olanzapine in treating non TRS has been confirmed. [7] In addition, studies has found that olanzapine is equally effective as clozapine in adult patients with TRS, schizophrenia like disorders, or schizoaffective disorders. [7-9] At present, there are many enhancement methods for TRS treatment, but each method has certain limitations. [9-12] For example, when combined with amisulpride, which is a selective dopamine D2/D3 receptor antagonist, it has good therapeutic effects on both positive and negative symptoms of schizophrenia. [9,10] Zink et al. [11] also confirmed that amisulpride enhanced olanzapine therapy has important clinical significance in treating TRS to improve clinical symptoms and cognitive function, with tolerability and safety. However, combination therapy may increase the risk of drug interactions, leading to an increased incidence of adverse reactions and individual differences in treatment efficacy. [12] Schmidt-Kraepelin et al. [12] found that the combination therapy of olanzapine and amisulpride did not effectively alleviate symptoms, but sexual dysfunction, weight and waist circumference increased significantly compared to the control group. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that has been proven effective in the treatment of psychiatric disorders. Zhu et al. [13] confirmed that rTMS can significantly improve cognitive function in schizophrenia patients with memory deficits. RTMS acts on the cerebral cortex through pulsed magnetic fields, altering the excitability of neurons and regulating brain neural function. [13] The dual regulation of 5-HT and dopamine systems by amisulpride and olanzapine helps restore balance between these two neurotransmitter systems. [9-11] However, current research on the combination of rTMS and amisulpride to enhance olanzapine in the treatment of TRS patients is still poor, and the effectiveness and safety of their combined use are not yet clear. Therefore, this retrospective analysis aims to investigate the value of rTMS combined with amisulpride in enhancing olanzapine treatment for TRS. We hope to provide some reference for the clinical treatment of TRS. MATERIALS AND METHODS This is a retrospective cohort analysis, sourced from records of TRS patients who received treatment with amisulpride enhanced olanzapine at the Third People's Hospital of Yongkang City from December 2022 to September 2023. Patients are divided into rTMS group and Non-rTMS group based on whether they receive combined rTMS treatment. Inclusion Criteria - Meets the diagnostic criteria of TRS; Having received at least two first or second-generation antipsychotic drugs with different chemical structures (at least one of which is a second-generation antipsychotic drug), and the therapeutic dose has reached the lower limit of the therapeutic dose (such as drugs other than clozapine that require a dose equivalent to 300-600mg/day of chlorpromazine), for at least 6 months, but the patient's positive symptoms have not significantly improved (such as a decrease of60 points; - Complete clinical data. Exclusion criteria - Patients with severe physical illnesses, such as heart, liver, and kidney dysfunction; - Patients with organic brain lesions; - Patients with drug abuse or alcohol dependence; - Pregnant or lactating women. Olanzapine (manufacturer: Jiangsu Enhua Pharmaceutical Co., Ltd.; specification: 5mg/tablet), taken orally, taken overnight before bedtime; Starting from 10 mg/d in the first week, 15 mg/d in the second week, and a maximum of 20 mg/d for the remaining six weeks. Amisulpride (Manufacturer: Shenzhen Pangu; China; 50 mg/tablet) is used for treatment, orally, taken overnight before bedtime; Starting from 200 mg/d in the first week, 400 mg/d in the second week, and a maximum of 600mg/d for the remaining six weeks. RTMS uses the M-50 Ultimate transcranial magnetic stimulator (Manufacturer: Shenzhen Yingzhi, China), with an "8" shaped stimulation coil and a stimulation site in the dorsolateral prefrontal cortex (dlPFC). Set the Resting Movement Threshold (RMT) with a stimulation intensity of 80% -110% and a frequency of 10Hz-20Hz; Each stimulus lasts for 4 seconds with an interval of 56 seconds between each stimulus. Treatment is given once a day for 20 minutes each time; Treat 5 days a week for a total of 8 weeks. Collect information: 1) Population characteristics, including age, gender, disease duration, educational level, family history, body mass index, and marital status. 2) The baseline and post-treatment PANSS scores include a positive symptom scale (7 items), a negative symptom scale (7 items), and a general psychopathological symptom scale (16 items), with each item scoring 1-7 points. The higher the score, the more severe the symptoms. [11] 3) Baseline and post-treatment Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores, including 12 items divided into five factor structures: attention, speech, visual breadth, immediate memory, and delayed memory; The higher the score, the better the patient's cognitive function. 3) The baseline and post-treatment World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) scores include four domains: social relationships, environment health, psychological well-being, and physical health, with a total score of 100 points for each dimension. The higher the score, the better the quality of life. 4) Adverse events include dizziness, dry mouth, constipation, insomnia, nausea and vomiting, extrapyramidal reactions, arrhythmia, etc. Statistical analysis: Based on a efficacy of 0.80 and a bilateral significance level of 0.05, each group requires at least 34 sample sizes. In this study, we assume a dropout rate of less than 15%. Each group requires a sample size of 40. Statistical analysis was conducted using PASW Statistics version 23.0 (SPSS, Inc., Chicago, USA). All data analysis was conducted using SPSS 24.0 software (IBM Corp, Armonk, NY, USA). Use Shapiro Wilk test to evaluate the normality of quantitative data. The quantitative data of normal distribution is represented by mean ± standard deviation (SD). Independent sample t-test is used for inter group comparison, and paired t-test is used for intra group comparison before and after; The quantitative data of non normal distribution are represented by median and interquartile range. Mann Whitney U test is used for inter group comparison, and Wilcoxon signed rank test is used for intra group comparison. The number of qualitative data cases is represented using chi square test or Fisher's exact probability method. The difference is statistically significant with P<0.05. RESULTS In this retrospective cohort study, a total of 133 patients met the criteria. Among them, 53.4% (71/133) were male. Age range: 18–63 years old, with an average age of 41.0 ± 11.1 years old; There were 64 patients in the rTMS group and 69 patients in the Non-rTMS group. There was no statistically significant difference in the comparison of demographic variables between the two groups (P > 0.05) (Table I). Table II shows the PANNS scores of two groups of patients before and after treatment. Table 2 shows the PANNS scores of two groups of patients before and after treatment. Before treatment, there was no statistically significant difference in the general psychopathological symptoms, positive symptom scores, negative symptom scores, and total scores between the rTMS group and the Non rTMS group (P > 0.05); After 8 weeks of treatment, the general symptom score, positive symptom score, negative symptom score, and PANSS total score of both groups were significantly reduced compared to before treatment (P < 0.05), and the scores and total score of each item in the rTMS group were lower than those in the Non rTMS group (P < 0.05). Table III shows the changes in RBANS scores between the two groups before and after treatment. Before treatment, there was no statistically significant difference in the immediate memory score, visuospatial/construction score, language score, attention score, delayed memory score, and total score between the two groups (P > 0.05). After 8 weeks of treatment, both groups showed significant increases in immediate memory score, visuospatial/construction score, language score, attention score, delayed memory score, and total score compared to before treatment (P < 0.05). In addition, except for the attention score, the rTMS group had significantly higher scores and total scores in all other dimensions compared to the Non rTMS group (P < 0.05). Table IV Changes in WHOQOL-BREF scores before and after treatment for both groups. Before treatment, there was no statistically significant difference in the scores of the social relationship score, environmental score, psychological score, and physiological score between the two groups (P > 0.05). After 8 weeks of treatment, the social relationship score, environmental score, psychological score, and physiological score in both groups significantly improved compared to before treatment, and all scores in the rTMS group were higher than those in the Non rTMS group (P < 0.05). Table V shows the occurrence of adverse events during the treatment period for two groups. In the rTMS group, there were 12 cases of dizziness, 5 cases of dry mouth, 4 cases of constipation, 4 cases of insomnia, 5 cases of nausea and vomiting, 2 cases of extrapyramidal reactions, and 6 cases of arrhythmia. The total number of adverse events was 31, with an incidence rate of 48.4% (31/64), of which 7 people experienced at least two types of adverse events; In the Non-rTMS group, there were 7 cases of dizziness, 5 cases of dry mouth, 2 cases of constipation, 8 cases of insomnia, 8 cases of nausea and vomiting, 5 cases of extrapyramidal reactions, and 4 cases of arrhythmia. The total number of adverse events was 31, with an incidence rate of 44.9% (31/69), of which 8 cases experienced at least two types of adverse events. There was no statistically significant difference in the total number of adverse events and occurrences between the two groups (P > 0.05).​ ​DISCUSSION In this retrospective cohort analysis, we compared the efficacy and safety of amisulpride in combination with rTMS alone to enhance olanzapine treatment for TRS. The results showed that rTMS combined with amisulpride enhanced olanzapine had higher benefits in improving patients' mental symptoms, cognitive function, and quality of life, and had equal safety. This is consistent with the research results of Liu et al. [14] and Zhao et al. [15] . The main reason is that the level of D2 receptor blockade in TRS patients has not reached a level that can produce a significant response, while amisulpride can selectively block D2/D3. [9-12,14,15] At the same time, rTMS utilizes magnetic field signal stimulation techniques to activate or inhibit cortical neural networks in the brain, thereby controlling patients' mental symptoms and achieving therapeutic goals. [13-15] It can be seen that combining rTMS enhanced therapy with drugs has broad prospects. After eight weeks of treatment, the PANNS scores in the rTMS group were significantly lower than those in the Non-rTMS group. This indicates that the combination of rTMS and amisulpride to enhance olanzapine treatment has more advantages in general symptoms, positive symptoms, and negative symptoms. This is consistent with the findings of Liu et al. [14] There are literature reports that when there is a poor response to olanzapine, relying solely on amisulpride to enhance treatment may not be able to fully correct the complex neurotransmitter imbalance in the patient's brain. [12,16] However, rTMS regulates neurotransmitter levels and improves brain function through magnetic pulses, synergizing with amisulpride to more effectively improve patients' psychiatric symptoms and reduce PANSS scores. [13-15,17] This is consistent with the findings of Lorentzen et al. [17] The results of this study showed that in terms of RBANS scores, except for attention, the rTMS group had significantly higher scores in dimensions such as immediate memory, visual breadth, speech function, and delayed memory than the Non-rTMS group, indicating that combination therapy has a more significant improvement in patients' cognitive function and can better help patients recover their memory and language expression abilities. The research results of Du et al. [18] indicate that rTMS improves visual memory and reduces negative symptoms of schizophrenia. Meanwhile, Xie et al. [19] confirmed that low-frequency rTMS can improve auditory hallucination speech function in schizophrenia. Mainly because rTMS stimulates the prefrontal cortex, which can increase dopamine release in this area and improve patients' cognitive function, including memory and language related executive functions. [18,19] In terms of quality of life, the WHOQOL-BREF score in the rTMS group was higher than that in the Non-rTMS group. This indicates that after rTMS combined with amisulpride enhances olanzapine treatment to improve patients' mental symptoms and cognitive function, their quality of life naturally improves. This enables patients to have better experiences in terms of physiology, psychology, social relationships, and environment. [18-20] In terms of safety, both groups reported the occurrence of adverse events, mainly dizziness, insomnia, and nausea and vomiting. But there was no significant difference in the total number of participants (48.4% in the rTMS group vs. 44.9% in the Non-rTMS group). This indicates that the combination of rTMS and amisulpride to enhance olanzapine is safe. This is consistent with previous studies. [18-23] In summary, this study analyzed the psychological symptoms, cognitive function, and quality of life, and confirmed that rTMS combined with amisulpride enhanced olanzapine treatment is effective and safe for TRS. The pathophysiology of TRS may be more complex than diseases that have a good therapeutic response to standard antipsychotic treatment. [23,24] The underlying pathophysiology may even be non dopaminergic. So we suggest combining rTMS treatment with amisulpride to enhance olanzapine therapy. This study has certain limitations. Firstly, this is a retrospective analysis of a single center and small sample size. Our findings require large sample sizes and multi center research validation. Secondly, basic experiments should be supplemented to explore the potential mechanisms of rTMS and its combination with amisulpride in enhancing olanzapine treatment for TRS, in order to better understand this therapy and TRS. Thirdly, the long-term efficacy and safety of rTMS and its combination with amisulpride to enhance olanzapine treatment have not been evaluated, and the long-term adverse reactions of the drug and the long-term neuroregulatory effects of rTMS are still unclear. Further research can be conducted on different stimulus parameters and drug dosage combinations to optimize treatment plans and improve treatment outcomes. CONCLUSION This study indicates that the combination of rTMS and amisulpride enhances olanzapine in the treatment of TRS, and has significant effects in improving patients' mental symptoms, cognitive function, and quality of life, while also being safe. This provides a new effective approach for the clinical treatment of TRS and has important clinical application value. However, due to certain limitations of this study, more high-quality research is still needed in the future to further validate and improve this treatment plan, in order to better serve clinical practice and help more patients recover their health.​ Abbreviations rTMS repetitive transcranial magnetic stimulation TRS resistant treatment-refractory schizophrenia PANSS Positive and Negative Symptom Rating Scale RBANS Repeatable Battery for the Assessment of Neuropsychological Status WHOQOL-BREF World Health Organization Quality of Life Questionnaire dlPFC dorsolateral prefrontal cortex RMT Resting Movement Threshold SD standard deviation BMI body mass index. Declarations Ethics approval and consent to participate The ethics committee of The Third People's Hospital of Yongkang City approved this study with the number YKSY-2023-LC-2023-9-19A1, Date: September 19th, 2023. All procedures involving human subjects adhered to the 1964 Declaration of Helsinki and its subsequent amendments or equivalent ethical standards. Given the retrospective nature of the study, informed consent was waived by the Ethical Committee of The Third People's Hospital of Yongkang City. All data were stored securely, and confidentiality was maintained throughout the study. Clinical trial number Not applicable. Consent for publication Not applicable. Data sharing statement No additional data are available. Conflict-of-interest statement All the authors report no relevant conflicts of interest for this article. Funding Jinhua Science and Technology Plan Project (2023-4-291). Authors’ contributions O.Y., L.Y., Y.L. designed the study; O.Y., L.Y., Y.L., M.Z., Q.H. collected the data; O.Y., L.Y., Q.H. performed the statistical analyses; O.Y., Q.H. interpreted the data; O.Y. wrote the manuscript; and Q.H. was awarded the grant. 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The safety and efficacy of adjunctive 20-Hz repetitive transcranial magnetic stimulation for treatment of negative symptoms in patients with schizophrenia: A double-blinded, randomized, sham-controlled study. Indian J Psychiatry. 2020 Jan-Feb;62(1):21-29. doi: 10.4103/psychiatry.IndianJPsychiatry_361_19 Whiskey E, Romano G, Elliott M, Campbell M, Anandarajah C, Taylor D, et al. Possible pharmacogenetic factors in clozapine treatment failure: a case report. Ther Adv Psychopharmacol. 2021 Jul 22;11:20451253211030844. doi: 10.1177/20451253211030844 Assion HJ, Reinbold H, Lemanski S, Basilowski M, Juckel G. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry . 2008;41(1):24-28. doi:10.1055/s-2007-993209 Barber S, Olotu U, Corsi M, Cipriani A. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. 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Published 2017 Mar 23. doi:10.1002/14651858.CD006324.pub3 Tables Table I Comparison of demographic characteristic variables between two groups Variables rTMS group (n=64) Non-rTMS group (n=69) t/Z/ χ 2 P Age, mean ± SD 39.8±11.5 42.1±10.7 -1.216 0.226 Male (Yes), n(%) 36 (56.3) 35 (50.7) 0.407 0.523 Disease duration (years), M(IQR) 23 (16-26.5) 24 (16-31) -1.374 0.169 Educational level, M(IQR) 9 (7-9) 9 (6-9) -0.060 0.952 Family history (yes), n(%) 19 (29.7) 26 (37.7) 0.948 0.330 BMI (kg/m²), mean ± SD 25.0±2.8 24.2±3.1 1.478 0.142 Marital status, n(%) 2.692 0.442 Unmarried 18 (28.1) 20 (29.0) Married 34 (53.1) 32 (46.4) Divorced 11 (17.2) 12 (17.4) Lose a spouse 1 (1.6) 5 (7.2) Table II Comparison of PANNS scores between two groups before and after treatment Time Variables rTMS group (n=64) Non-rTMS group (n=69) Z/t P Before intervention General psychopathology subscores 42.5 (32-51.5) 43 (37-54) -0.797 0.425 Positive symptom subscores 25.1±3.1 24.4±3.7 1.310 0.193 Negative symptom subscores 23 (22-25) 25 (22-27) -1.699 0.089 Total score 90.5±11.4 92.1±12.4 -0.787 0.433 After intervention General psychopathology subscores 20.5 (19-23.5) # 25 (22-29) # -4.868 <0.001 Positive symptom subscores 15 (13-18) # 19 (16-20) # -4.353 <0.001 Negative symptom subscores 15 (12-16) # 16 (14-20) # -2.995 0.003 Total score 51.5 (48.5-54.5) # 61 (56-66) # -6.286 <0.001 Compared with before treatment in the same group, # P ＜0.05 Table III Comparison of RBANS scores before and after treatment between two groups Time Variables rTMS group (n=64) Non-rTMS group (n=69) t/Z P Before intervention Immediate memory 61.8±8.7 60.1±8.0 1.185 0.238 Visuospatial/construction 67.2±10.8 65.8±9.2 0.848 0.398 Language 71.1±13.3 73.1±10.7 -0.919 0.360 Attention 70.9±9.3 69.3±11.4 0.876 0.382 Delayed memory 60.8±8.0 58.9±8.1 1.416 0.159 Total score 63.5 (53-71.5) 62 (53-65) -0.692 0.489 After intervention Immediate memory 70.0±9.5 # 64.6±7.5 # 3.637 <0.001 Visuospatial/construction 72.4±11.4 # 67.5±9.8 # 2.660 0.009 Language 80.7±14.7 # 74.7±10.0 # 2.772 0.006 Attention 72.3±8.4 # 70.4±9.8 # 1.178 0.241 Delayed memory 67.4±9.7 # 61.9±9.4 # 3.334 <0.001 Total score 69.5 (59-81) # 65 (56-68) # -6.286 <0.001 Compared with before treatment in the same group, # P ＜0.05 Table IV Comparison of WHOQOL-BREF scores between two groups before and after treatment Time Variables rTMS group (n=64) Non-rTMS group (n=69) Z P Before intervention Social relationships 49 (45-52.5) 50 (45-54) -0.912 0.362 Environment health 49.5 (46.5-54) 50 (47-56) -1.038 0.299 Psychological well-being 46.5 (43-50) 45 (41-50) -1.251 0.211 Physical health 51.5 (47-55) 49 (45-56) -1.439 0.150 After intervention Social relationships 74 (69-79.5) 69 (63-74) -3.503 <0.001 Environment health 72.5±5.9 67.7±6.9 4.300 <0.001 Psychological well-being 74 (69-77.5) 70 (64-75) -3.842 <0.001 Physical health 76 (71-79) 70 (66-77) -3.869 <0.001 Table V: Occurrence of adverse events in two groups Adverse event rTMS group (n=64) Non-rTMS group (n=69) Z P Dizzy 12 (18.8) 7 (10.1) 2.008 0.156 a Dry mouth 5 (7.8) 5 (7.2) 0.015 0.902 b Constipation 4 (6.3) 2 (2.9) 0.866 0.352 b Insomnia 4 (6.3) 8 (11.6) 1.155 0.282 a Nausea and vomiting 5 (7.8) 8 (11.6) 0.538 0.463 a Extrapyramidal syndrome 2 (3.1) 5 (7.2) 1.131 0.288 b Arrhythmia 6 (9.4) 4 (5.8) 0.611 0.434 b Total number of occurrences 31 (48.4) 31 (44.9) 0.164 0.685 a a Pearson’s Chi-square test; b Fisher’s Exact Test. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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effectively block dopamine D2 receptors and \u0026nbsp;5-hydroxytryptamine (5-HT2A) receptors, thereby improving patients' symptoms. \u003csup\u003e[3,4]\u0026nbsp;\u003c/sup\u003eHowever, there are still 30% -50% of patients whose symptoms have not been effectively improved after treatment with clozapine, and even have recurrent or worsening conditions. \u003csup\u003e[3-6]\u0026nbsp;\u003c/sup\u003eFor some patients, the use of clozapine has been excluded due to clinical contraindications, including discontinuation of clozapine due to adverse events. Therefore, alternative treatment is needed for those who do not want to start using clozapine due to concerns about side effects or the need for monitoring. \u003csup\u003e[4-6]\u0026nbsp;\u003c/sup\u003eThe effectiveness of olanzapine in treating non TRS has been confirmed. \u003csup\u003e[7]\u0026nbsp;\u003c/sup\u003eIn addition, studies has found that olanzapine is equally effective as clozapine in adult patients with TRS, schizophrenia like disorders, or schizoaffective disorders. \u003csup\u003e[7-9]\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAt present, there are many enhancement methods for TRS treatment, but each method has certain limitations. \u003csup\u003e[9-12]\u003c/sup\u003e For example, when combined with amisulpride, which is a selective dopamine D2/D3 receptor antagonist, it has good therapeutic effects on both positive and negative symptoms of schizophrenia. \u003csup\u003e[9,10]\u003c/sup\u003e Zink et al. \u003csup\u003e[11]\u003c/sup\u003e also confirmed that amisulpride enhanced olanzapine therapy has important clinical significance in treating TRS to improve clinical symptoms and cognitive function, with tolerability and safety. However, combination therapy may increase the risk of drug interactions, leading to an increased incidence of adverse reactions and individual differences in treatment efficacy. \u003csup\u003e[12]\u003c/sup\u003e Schmidt-Kraepelin et al. \u003csup\u003e[12]\u003c/sup\u003e found that the combination therapy of olanzapine and amisulpride did not effectively alleviate symptoms, but sexual dysfunction, weight and waist circumference increased significantly compared to the control group.\u003c/p\u003e\n\u003cp\u003eRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that has been proven effective in the treatment of psychiatric disorders. Zhu et al. \u003csup\u003e[13]\u0026nbsp;\u003c/sup\u003econfirmed that rTMS can significantly improve cognitive function in schizophrenia patients with memory deficits. RTMS acts on the cerebral cortex through pulsed magnetic fields, altering the excitability of neurons and regulating brain neural function. \u003csup\u003e[13]\u0026nbsp;\u003c/sup\u003eThe dual regulation of 5-HT and dopamine systems by amisulpride and olanzapine helps restore balance between these two neurotransmitter systems. \u003csup\u003e[9-11]\u0026nbsp;\u003c/sup\u003eHowever, current research on the combination of rTMS and amisulpride to enhance olanzapine in the treatment of TRS patients is still poor, and the effectiveness and safety of their combined use are not yet clear.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTherefore, this retrospective analysis aims to investigate the value of rTMS combined with amisulpride in enhancing olanzapine treatment for TRS. We hope to provide some reference for the clinical treatment of TRS. \u0026nbsp;\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis is a retrospective cohort analysis, sourced from records of TRS patients who received treatment with amisulpride enhanced olanzapine at the Third People's Hospital of Yongkang City from December 2022 to September 2023. Patients are divided into rTMS group and Non-rTMS group based on whether they receive combined rTMS treatment.\u003c/p\u003e\n\u003cp\u003eInclusion Criteria\u003c/p\u003e\n\u003cp\u003e- Meets the diagnostic criteria of TRS; Having received at least two first or second-generation antipsychotic drugs with different chemical structures (at least one of which is a second-generation antipsychotic drug), and the therapeutic dose has reached the lower limit of the therapeutic dose (such as drugs other than clozapine that require a dose equivalent to 300-600mg/day of chlorpromazine), for at least 6 months, but the patient's positive symptoms have not significantly improved (such as a decrease of\u0026lt;20% -30% in the positive symptom score of the Positive and Negative Symptom Scale (PANSS));\u003csup\u003e[1]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e- Age between 18 and 65 years old;\u003c/p\u003e\n\u003cp\u003e- Baseline PANSS score\u0026gt;60 points;\u003c/p\u003e\n\u003cp\u003e- Complete clinical data.\u003c/p\u003e\n\u003cp\u003eExclusion criteria\u003c/p\u003e\n\u003cp\u003e- Patients with severe physical illnesses, such as heart, liver, and kidney dysfunction;\u003c/p\u003e\n\u003cp\u003e- Patients with organic brain lesions;\u003c/p\u003e\n\u003cp\u003e- Patients with drug abuse or alcohol dependence;\u003c/p\u003e\n\u003cp\u003e- Pregnant or lactating women.\u003c/p\u003e\n\u003cp\u003eOlanzapine (manufacturer: Jiangsu Enhua Pharmaceutical Co., Ltd.; specification: 5mg/tablet), taken orally, taken overnight before bedtime; Starting from 10 mg/d in the first week, 15 mg/d in the second week, and a maximum of 20 mg/d for the remaining six weeks.\u003c/p\u003e\n\u003cp\u003eAmisulpride (Manufacturer: Shenzhen Pangu; China; 50 mg/tablet) is used for treatment, orally, taken overnight before bedtime; Starting from 200 mg/d in the first week, 400 mg/d in the second week, and a maximum of 600mg/d for the remaining six weeks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRTMS uses the M-50 Ultimate transcranial magnetic stimulator (Manufacturer: Shenzhen Yingzhi, China), with an \"8\" shaped stimulation coil and a stimulation site in the dorsolateral prefrontal cortex (dlPFC). Set the Resting Movement Threshold (RMT) with a stimulation intensity of 80% -110% and a frequency of 10Hz-20Hz; Each stimulus lasts for 4 seconds with an interval of 56 seconds between each stimulus. Treatment is given once a day for 20 minutes each time; Treat 5 days a week for a total of 8 weeks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCollect information: 1) Population characteristics, including age, gender, disease duration, educational level, family history, body mass index, and marital status. 2) The baseline and post-treatment PANSS scores include a positive symptom scale (7 items), a negative symptom scale (7 items), and a general psychopathological symptom scale (16 items), with each item scoring 1-7 points. The higher the score, the more severe the symptoms.\u003csup\u003e\u0026nbsp;[11]\u0026nbsp;\u003c/sup\u003e3) Baseline and post-treatment Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores, including 12 items divided into five factor structures: attention, speech, visual breadth, immediate memory, and delayed memory; The higher the score, the better the patient's cognitive function. 3) The baseline and post-treatment World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) scores include four domains: social relationships, environment health, psychological well-being, and physical health, with a total score of 100 points for each dimension. The higher the score, the better the quality of life. 4) Adverse events include dizziness, dry mouth, constipation, insomnia, nausea and vomiting, extrapyramidal reactions, arrhythmia, etc.\u003c/p\u003e\n\u003cp\u003eStatistical analysis: Based on a efficacy of 0.80 and a bilateral significance level of 0.05, each group requires at least 34 sample sizes. In this study, we assume a dropout rate of less than 15%. Each group requires a sample size of 40. Statistical analysis was conducted using PASW Statistics version 23.0 (SPSS, Inc., Chicago, USA). All data analysis was conducted using SPSS 24.0 software (IBM Corp, Armonk, NY, USA). Use Shapiro Wilk test to evaluate the normality of quantitative data. The quantitative data of normal distribution is represented by mean ± standard deviation (SD). Independent sample t-test is used for inter group comparison, and paired t-test is used for intra group comparison before and after; The quantitative data of non normal distribution are represented by median and interquartile range. Mann Whitney U test is used for inter group comparison, and Wilcoxon signed rank test is used for intra group comparison. The number of qualitative data cases is represented using chi square test or Fisher's exact probability method. The difference is statistically significant with P\u0026lt;0.05.\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eIn this retrospective cohort study, a total of 133 patients met the criteria. Among them, 53.4% (71/133) were male. Age range: 18\u0026ndash;63 years old, with an average age of 41.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.1 years old; There were 64 patients in the rTMS group and 69 patients in the Non-rTMS group. There was no statistically significant difference in the comparison of demographic variables between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table I).\u003c/p\u003e\u003cp\u003eTable II shows the PANNS scores of two groups of patients before and after treatment. Table\u0026nbsp;2 shows the PANNS scores of two groups of patients before and after treatment. Before treatment, there was no statistically significant difference in the general psychopathological symptoms, positive symptom scores, negative symptom scores, and total scores between the rTMS group and the Non rTMS group (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05); After 8 weeks of treatment, the general symptom score, positive symptom score, negative symptom score, and PANSS total score of both groups were significantly reduced compared to before treatment (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the scores and total score of each item in the rTMS group were lower than those in the Non rTMS group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eTable III shows the changes in RBANS scores between the two groups before and after treatment. Before treatment, there was no statistically significant difference in the immediate memory score, visuospatial/construction score, language score, attention score, delayed memory score, and total score between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After 8 weeks of treatment, both groups showed significant increases in immediate memory score, visuospatial/construction score, language score, attention score, delayed memory score, and total score compared to before treatment (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In addition, except for the attention score, the rTMS group had significantly higher scores and total scores in all other dimensions compared to the Non rTMS group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eTable IV Changes in WHOQOL-BREF scores before and after treatment for both groups. Before treatment, there was no statistically significant difference in the scores of the social relationship score, environmental score, psychological score, and physiological score between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After 8 weeks of treatment, the social relationship score, environmental score, psychological score, and physiological score in both groups significantly improved compared to before treatment, and all scores in the rTMS group were higher than those in the Non rTMS group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eTable V shows the occurrence of adverse events during the treatment period for two groups. In the rTMS group, there were 12 cases of dizziness, 5 cases of dry mouth, 4 cases of constipation, 4 cases of insomnia, 5 cases of nausea and vomiting, 2 cases of extrapyramidal reactions, and 6 cases of arrhythmia. The total number of adverse events was 31, with an incidence rate of 48.4% (31/64), of which 7 people experienced at least two types of adverse events; In the Non-rTMS group, there were 7 cases of dizziness, 5 cases of dry mouth, 2 cases of constipation, 8 cases of insomnia, 8 cases of nausea and vomiting, 5 cases of extrapyramidal reactions, and 4 cases of arrhythmia. The total number of adverse events was 31, with an incidence rate of 44.9% (31/69), of which 8 cases experienced at least two types of adverse events. There was no statistically significant difference in the total number of adverse events and occurrences between the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).​\u003c/p\u003e"},{"header":"​DISCUSSION","content":"\u003cp\u003eIn this retrospective cohort analysis, we compared the efficacy and safety of amisulpride in combination with rTMS alone to enhance olanzapine treatment for TRS. The results showed that rTMS combined with amisulpride enhanced olanzapine had higher benefits in improving patients' mental symptoms, cognitive function, and quality of life, and had equal safety. This is consistent with the research results of Liu et al. \u003csup\u003e[14]\u0026nbsp;\u003c/sup\u003eand Zhao et al. \u003csup\u003e[15]\u003c/sup\u003e. The main reason is that the level of D2 receptor blockade in TRS patients has not reached a level that can produce a significant response, while amisulpride can selectively block D2/D3. \u003csup\u003e[9-12,14,15]\u0026nbsp;\u003c/sup\u003eAt the same time, rTMS utilizes magnetic field signal stimulation techniques to activate or inhibit cortical neural networks in the brain, thereby controlling patients' mental symptoms and achieving therapeutic goals.\u003csup\u003e\u0026nbsp;[13-15]\u003c/sup\u003e It can be seen that combining rTMS enhanced therapy with drugs has broad prospects.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;After eight weeks of treatment, the PANNS scores in the rTMS group were significantly lower than those in the Non-rTMS group. This indicates that the combination of rTMS and amisulpride to enhance olanzapine treatment has more advantages in general symptoms, positive symptoms, and negative symptoms. This is consistent with the findings of Liu et al. \u003csup\u003e[14]\u0026nbsp;\u003c/sup\u003eThere are literature reports that when there is a poor response to olanzapine, relying solely on amisulpride to enhance treatment may not be able to fully correct the complex neurotransmitter imbalance in the patient's brain. \u003csup\u003e[12,16]\u003c/sup\u003e However, rTMS regulates neurotransmitter levels and improves brain function through magnetic pulses, synergizing with amisulpride to more effectively improve patients' psychiatric symptoms and reduce PANSS scores. \u003csup\u003e[13-15,17]\u0026nbsp;\u003c/sup\u003eThis is consistent with the findings of Lorentzen et al. \u003csup\u003e[17]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe results of this study showed that in terms of RBANS scores, except for attention, the rTMS group had significantly higher scores in dimensions such as immediate memory, visual breadth, speech function, and delayed memory than the Non-rTMS group, indicating that combination therapy has a more significant improvement in patients' cognitive function and can better help patients recover their memory and language expression abilities. The research results of Du et al. \u003csup\u003e[18]\u0026nbsp;\u003c/sup\u003eindicate that rTMS improves visual memory and reduces negative symptoms of schizophrenia. Meanwhile, Xie et al.\u003csup\u003e\u0026nbsp;[19]\u003c/sup\u003e confirmed that low-frequency rTMS can improve auditory hallucination speech function in schizophrenia. Mainly because rTMS stimulates the prefrontal cortex, which can increase dopamine release in this area and improve patients' cognitive function, including memory and language related executive functions. \u003csup\u003e[18,19]\u003c/sup\u003e In terms of quality of life, the WHOQOL-BREF score in the rTMS group was higher than that in the Non-rTMS group. This indicates that after rTMS combined with amisulpride enhances olanzapine treatment to improve patients' mental symptoms and cognitive function, their quality of life naturally improves. This enables patients to have better experiences in terms of physiology, psychology, social relationships, and environment. \u003csup\u003e[18-20]\u0026nbsp;\u003c/sup\u003eIn terms of safety, both groups reported the occurrence of adverse events, mainly dizziness, insomnia, and nausea and vomiting. But there was no significant difference in the total number of participants (48.4% in the rTMS group vs. 44.9% in the Non-rTMS group). This indicates that the combination of rTMS and amisulpride to enhance olanzapine is safe. This is consistent with previous studies.\u003csup\u003e\u0026nbsp;[18-23]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn summary, this study analyzed the psychological symptoms, cognitive function, and quality of life, and confirmed that rTMS combined with amisulpride enhanced olanzapine treatment is effective and safe for TRS. The pathophysiology of TRS may be more complex than diseases that have a good therapeutic response to standard antipsychotic treatment. \u003csup\u003e[23,24]\u003c/sup\u003e The underlying pathophysiology may even be non dopaminergic. So we suggest combining rTMS treatment with amisulpride to enhance olanzapine therapy.\u003c/p\u003e\n\u003cp\u003eThis study has certain limitations. Firstly, this is a retrospective analysis of a single center and small sample size. Our findings require large sample sizes and multi center research validation. Secondly, basic experiments should be supplemented to explore the potential mechanisms of rTMS and its combination with amisulpride in enhancing olanzapine treatment for TRS, in order to better understand this therapy and TRS. Thirdly, the long-term efficacy and safety of rTMS and its combination with amisulpride to enhance olanzapine treatment have not been evaluated, and the long-term adverse reactions of the drug and the long-term neuroregulatory effects of rTMS are still unclear. Further research can be conducted on different stimulus parameters and drug dosage combinations to optimize treatment plans and improve treatment outcomes.\u0026nbsp;\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis study indicates that the combination of rTMS and amisulpride enhances olanzapine in the treatment of TRS, and has significant effects in improving patients' mental symptoms, cognitive function, and quality of life, while also being safe. This provides a new effective approach for the clinical treatment of TRS and has important clinical application value. However, due to certain limitations of this study, more high-quality research is still needed in the future to further validate and improve this treatment plan, in order to better serve clinical practice and help more patients recover their health.​\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003erTMS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erepetitive transcranial magnetic stimulation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTRS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eresistant treatment-refractory schizophrenia\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePANSS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePositive and Negative Symptom Rating Scale\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRBANS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRepeatable Battery for the Assessment of Neuropsychological Status\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHOQOL-BREF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWorld Health Organization Quality of Life Questionnaire\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003edlPFC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003edorsolateral prefrontal cortex\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRMT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eResting Movement Threshold\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003estandard deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebody mass index.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethics committee of The Third People's Hospital of Yongkang City approved this study with the number YKSY-2023-LC-2023-9-19A1, Date: September 19th, 2023. All procedures involving human subjects adhered to the 1964 Declaration of Helsinki and its subsequent amendments or equivalent ethical standards. Given the retrospective nature of the study, informed consent was waived by the Ethical Committee of The Third People's Hospital of Yongkang City. All data were stored securely, and confidentiality was maintained throughout the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sharing statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo additional data are available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict-of-interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors report no relevant conflicts of interest for this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJinhua Science and Technology Plan Project (2023-4-291).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eO.Y., L.Y., Y.L. designed the study; O.Y., L.Y., Y.L., M.Z., Q.H. collected the data; O.Y., L.Y., Q.H. performed the statistical analyses; O.Y., Q.H. interpreted the data; O.Y. wrote the manuscript; and Q.H. was awarded the grant. All authors contributed to the final manuscript and are known.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSolmi M, Seitidis G, Mavridis D, Correll CU, Dragioti E, Guimond S, et al. Incidence, prevalence, and global burden of schizophrenia - data, with critical appraisal, from the Global Burden of Disease (GBD) 2019. Mol Psychiatry. 2023 Dec;28(12):5319-5327. doi: 10.1038/s41380-023-02138-4\u003c/li\u003e\n\u003cli\u003eKane JM, Agid O, Baldwin ML, Howes O, Lindenmayer JP, Marder S, et al. Clinical Guidance on the Identification and Management of Treatment-Resistant Schizophrenia. J Clin Psychiatry. 2019 Mar 5;80(2):18com12123. doi: 10.4088/JCP.18com12123\u003c/li\u003e\n\u003cli\u003eCorrell CU, Howes OD. Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options. \u003cem\u003eJ Clin Psychiatry\u003c/em\u003e. 2021;82(5):MY20096AH1C. Published 2021 Sep 7. doi:10.4088/JCP.MY20096AH1C\u003c/li\u003e\n\u003cli\u003eYing J, Chew QH, McIntyre RS, Sim K. Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review. \u003cem\u003eGenes (Basel)\u003c/em\u003e. 2023;14(3):689. Published 2023 Mar 10. doi:10.3390/genes14030689\u003c/li\u003e\n\u003cli\u003eMorrison AP, Pyle M, Gumley A, Schwannauer M, Turkington D, MacLennan G, et al. Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. Lancet Psychiatry. 2018 Aug;5(8):633-643. doi: 10.1016/S2215-0366(18)30184-6\u003c/li\u003e\n\u003cli\u003eSiskind DJ, Lee M, Ravindran A, Zhang Q, Ma E, Motamarri B, et al. Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis. Aust N Z J Psychiatry. 2018 Aug;52(8):751-767. doi: 10.1177/0004867418772351\u003c/li\u003e\n\u003cli\u003eLi J, Chen F. Efficacy and safety evaluation of olanzapine treatment for schizophrenia patients: A retrospective data analysis. Arch Psychiatr Nurs. 2025;54:26-30. doi:10.1016/j.apnu.2024.12.005\u003c/li\u003e\n\u003cli\u003eSamara MT, Dold M, Gianatsi M, Nikolakopoulou A, Helfer B, Salanti G, et al. Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis. JAMA Psychiatry. 2016 Mar;73(3):199-210. doi: 10.1001/jamapsychiatry.2015.2955\u003c/li\u003e\n\u003cli\u003eZhu MH, Liu ZJ, Hu QY, Yang JY, Jin Y, Zhu N, et al. Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial. Mil Med Res. 2022 Oct 18;9(1):59. doi: 10.1186/s40779-022-00420-0\u003c/li\u003e\n\u003cli\u003eBarnes TRE, Leeson V, Paton C, Marston L, Osborn DP, Kumar R, et al. Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: a double-blind, placebo-controlled trial. Ther Adv Psychopharmacol. 2018 Jul;8(7):185-197. doi: 10.1177/2045125318762365\u003c/li\u003e\n\u003cli\u003eZink M, Henn FA, Thome J. Combination of amisulpride and olanzapine in treatment-resistant schizophrenic psychoses. Eur Psychiatry. 2004;19(1):56-58. doi:10.1016/j.eurpsy.2003.09.002\u003c/li\u003e\n\u003cli\u003eSchmidt-Kraepelin C, Feyerabend S, Engelke C, Riesbeck M, Meisenzahl-Lechner E, Verde PE, et al. Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial. Lancet Psychiatry. 2022 Apr;9(4):291-306. doi: 10.1016/S2215-0366(22)00032-3\u003c/li\u003e\n\u003cli\u003eZhu X, Huang C, Fan H, Fan F, Zhao Y, Xiu M, et al. The effect of transcranial direct current stimulation combined with working memory training on working memory deficits in schizophrenic patients: study protocol for a randomized controlled trial. Trials. 2022;23:826. doi: org/10.1186/s13063-022-06776-x\u003c/li\u003e\n\u003cli\u003eLiu JL, Tan ZM, Jiao SJ. Repetitive transcranial magnetic stimulation combined with olanzapine and amisulpride for treatment-refractory schizophrenia. World J Psychiatry. 2023;13(7):453-460. Published 2023 Jul 19. doi:10.5498/wjp.v13.i7.453\u003c/li\u003e\n\u003cli\u003eZhao XY, Tang XW, Xiao WH, Zhang W. The effect of repetitive transcranial magnetic stimulation combined with amisulpride in the treatment of schizophrenia and its impact on cognitive function. J of Clin Med in Practice. 2022, 26(23):89-91.doi: 10.7619 /jcmp.20222325\u003c/li\u003e\n\u003cli\u003eWoo YS, Park SY, Yoon BH, Choi WS, Wang SM, Bahk WM. Amisulpride Augmentation in Schizophrenia Patients with Poor Response to Olanzapine: A 4-week, Randomized, Rater-Blind, Controlled, Pilot Study. Clin Psychopharmacol Neurosci. 2022 Aug 31;20(3):567-572. doi: 10.9758/cpn.2022.20.3.567\u003c/li\u003e\n\u003cli\u003eLorentzen R, Nguyen TD, McGirr A, Hieronymus F, \u0026Oslash;stergaard SD. The efficacy of transcranial magnetic stimulation (TMS) for negative symptoms in schizophrenia: a systematic review and meta-analysis. Schizophrenia (Heidelb). 2022 Apr 9;8(1):35. doi: 10.1038/s41537-022-00248-6\u003c/li\u003e\n\u003cli\u003eDu XD, Li Z, Yuan N, Yin M, Zhao XL, Lv XL, et al. Delayed improvements in visual memory task performance among chronic schizophrenia patients after high-frequency repetitive transcranial magnetic stimulation. World J Psychiatry. 2022 Sep 19;12(9):1169-1182. doi: 10.5498/wjp.v12.i9.1169\u003c/li\u003e\n\u003cli\u003eXie Y, Li C, Guan M, Zhang T, Ma C, Wang Z, et al. The efficacy of low frequency repetitive transcial magnetic stimulation for treating auditory verbal hallucinations in schizophrenia: Insights from functional gradient analyses. Heliyon. 2024 Apr 24;10(9):e30194. doi: 10.1016/j.heliyon.2024.e30194\u003c/li\u003e\n\u003cli\u003eKousar T, Riaz MN. Effect of positive and negative symptoms on schizophrenia related quality of life of hospitalized schizophrenic patients at Sargodha and Lahore: Moderating role of neuropsychiatric symptoms. \u003cem\u003eJ Pak Med Assoc\u003c/em\u003e. 2021;71(1(A)):4-7. doi:10.47391/JPMA.1105\u003c/li\u003e\n\u003cli\u003eSingh S, Kumar N, Verma R, Nehra A. The safety and efficacy of adjunctive 20-Hz repetitive transcranial magnetic stimulation for treatment of negative symptoms in patients with schizophrenia: A double-blinded, randomized, sham-controlled study. Indian J Psychiatry. 2020 Jan-Feb;62(1):21-29. doi: 10.4103/psychiatry.IndianJPsychiatry_361_19\u003c/li\u003e\n\u003cli\u003eWhiskey E, Romano G, Elliott M, Campbell M, Anandarajah C, Taylor D, et al. Possible pharmacogenetic factors in clozapine treatment failure: a case report. Ther Adv Psychopharmacol. 2021 Jul 22;11:20451253211030844. doi: 10.1177/20451253211030844\u003c/li\u003e\n\u003cli\u003eAssion HJ, Reinbold H, Lemanski S, Basilowski M, Juckel G. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial. \u003cem\u003ePharmacopsychiatry\u003c/em\u003e. 2008;41(1):24-28. doi:10.1055/s-2007-993209\u003c/li\u003e\n\u003cli\u003eBarber S, Olotu U, Corsi M, Cipriani A. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. \u003cem\u003eCochrane Database Syst Rev\u003c/em\u003e. 2017;3(3):CD006324. Published 2017 Mar 23. doi:10.1002/14651858.CD006324.pub3\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable I Comparison of demographic characteristic variables between two groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eVariables \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003erTMS group (n=64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003eNon-rTMS group (n=69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003et/Z/\u003cem\u003e\u0026chi;\u003c/em\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eAge, mean\u0026nbsp;\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e39.8\u0026plusmn;11.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e42.1\u0026plusmn;10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-1.216\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.226\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eMale (Yes), n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e36 (56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e35 (50.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.407\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.523\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eDisease duration (years), M(IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e23 (16-26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e24 (16-31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-1.374\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eEducational level, M(IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e9 (7-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e9 (6-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.952\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eFamily history (yes), n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e19 (29.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e26 (37.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.948\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.330\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eBMI (kg/m\u0026sup2;), mean\u0026nbsp;\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e25.0\u0026plusmn;2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e24.2\u0026plusmn;3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.478\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eMarital status, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.442\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eUnmarried\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e18 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e20 (29.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eMarried\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e34 (53.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e32 (46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eDivorced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e11 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e12 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003eLose a spouse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e5 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable II Comparison of PANNS scores between two groups before and after treatment\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eTime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eVariables\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003erTMS group (n=64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eNon-rTMS group (n=69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eZ/t\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 15px;\"\u003e\n \u003cp\u003eBefore intervention\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eGeneral psychopathology subscores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e42.5 (32-51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e43 (37-54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-0.797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.425\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003ePositive symptom subscores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e25.1\u0026plusmn;3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e24.4\u0026plusmn;3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eNegative symptom subscores\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e23 (22-25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e25 (22-27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-1.699\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eTotal score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e90.5\u0026plusmn;11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e92.1\u0026plusmn;12.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-0.787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.433\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAfter intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eGeneral psychopathology subscores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e20.5 (19-23.5)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e25 (22-29)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-4.868\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003ePositive symptom subscores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e15 (13-18)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e19 (16-20)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-4.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eNegative symptom subscores\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e15 (12-16)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e16 (14-20)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-2.995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eTotal score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e51.5 (48.5-54.5)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e61 (56-66)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-6.286\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCompared with before treatment in the same group,\u0026nbsp;\u003csup\u003e#\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e＜0.05\u003c/p\u003e\n\u003cp\u003eTable III Comparison of RBANS scores before and after treatment between two groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eTime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eVariables\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003erTMS group (n=64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003eNon-rTMS group (n=69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003et/Z\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 76px;\"\u003e\n \u003cp\u003eBefore intervention\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eImmediate memory\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e61.8\u0026plusmn;8.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e60.1\u0026plusmn;8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1.185\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.238\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eVisuospatial/construction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e67.2\u0026plusmn;10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e65.8\u0026plusmn;9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.848\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.398\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eLanguage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e71.1\u0026plusmn;13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e73.1\u0026plusmn;10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e-0.919\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.360\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eAttention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e70.9\u0026plusmn;9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e69.3\u0026plusmn;11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.876\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eDelayed memory\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e60.8\u0026plusmn;8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e58.9\u0026plusmn;8.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1.416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eTotal score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e63.5 (53-71.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e62 (53-65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e-0.692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.489\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 76px;\"\u003e\n \u003cp\u003eAfter intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eImmediate memory\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e70.0\u0026plusmn;9.5\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e64.6\u0026plusmn;7.5\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3.637\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eVisuospatial/construction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e72.4\u0026plusmn;11.4\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e67.5\u0026plusmn;9.8\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2.660\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eLanguage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e80.7\u0026plusmn;14.7\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e74.7\u0026plusmn;10.0\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2.772\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eAttention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e72.3\u0026plusmn;8.4\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e70.4\u0026plusmn;9.8\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1.178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.241\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eDelayed memory\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e67.4\u0026plusmn;9.7\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e61.9\u0026plusmn;9.4\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3.334\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eTotal score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e69.5 (59-81)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e65 (56-68)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e-6.286\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCompared with before treatment in the same group, \u003csup\u003e#\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e＜0.05\u003c/p\u003e\n\u003cp\u003eTable IV Comparison of WHOQOL-BREF scores between two groups before and after treatment\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eTime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eVariables\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003erTMS group (n=64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eNon-rTMS group (n=69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003eZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 76px;\"\u003e\n \u003cp\u003eBefore intervention\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eSocial relationships\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e49 (45-52.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e50 (45-54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e-0.912\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e0.362\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eEnvironment health\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e49.5 (46.5-54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e50 (47-56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e-1.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003ePsychological well-being\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e46.5 (43-50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e45 (41-50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e-1.251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e0.211\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003ePhysical health\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e51.5 (47-55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e49 (45-56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e-1.439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e0.150\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 76px;\"\u003e\n \u003cp\u003eAfter intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eSocial relationships\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e74 (69-79.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e69 (63-74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e-3.503\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eEnvironment health\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e72.5\u0026plusmn;5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e67.7\u0026plusmn;6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e4.300\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003ePsychological well-being\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e74 (69-77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e70 (64-75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e-3.842\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003ePhysical health\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e76 (71-79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e70 (66-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e-3.869\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable V: Occurrence of adverse events in two groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eAdverse event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003erTMS group (n=64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eNon-rTMS group (n=69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eDizzy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e12 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e7 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.156\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eDry mouth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e5 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e5 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.902\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e4 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e2 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.866\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.352\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e4 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e8 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.282\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eNausea and vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e5 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e8 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.538\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.463\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eExtrapyramidal syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e2 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e5 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.288\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eArrhythmia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e6 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e4 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.611\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.434\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eTotal number of occurrences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e31 (48.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e31 (44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.685\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e\u003cem\u003e\u0026nbsp;Pearson\u0026rsquo;s Chi-square test; \u003csup\u003eb\u003c/sup\u003eFisher\u0026rsquo;s Exact Test.\u003c/em\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Repetitive transcranial magnetic stimulation, amisulpride enhancement therapy, olanzapine, resistant treatment-refractory, schizophrenia","lastPublishedDoi":"10.21203/rs.3.rs-7377896/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7377896/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/em\u003e Repetitive transcranial magnetic stimulation (rTMS) is a widely used enhancement therapy for schizophrenia, but there are few controlled studies on the combination of rTMS and amisulpride enhancement therapy. The aim of this study is to explore the value of rTMS combined with amisulpride enhanced olanzapine therapy for resistant treatment-refractory schizophrenia (TRS) patients.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e\u003c/em\u003eWe conducted a retrospective analysis based on records of TRS patients who received amisulpride enhanced olanzapine treatment at the Third People's Hospital of Yongkang City from December 2022 to September 2023. Patients are divided into rTMS group and Non-rTMS group based on whether they receive combined rTMS treatment. We examined the patient's Positive and Negative Symptom Rating Scale (PANSS) scores, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores, World Health Organization Quality of Life Questionnaire (WHOQOL-BREF), and incidence of adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/em\u003e After treatment, the scores of PANNS in both groups significantly decreased, and the rTMS group was lower than the Non-rTMS group (P\u0026lt;0.05); The scores of RBANS and WHOQOL-BREF in both groups significantly increased (P\u0026lt;0.05); Except for the attention sub item, all other sub scores in the rTMS group were higher than those in the Non-rTMS group (P\u0026lt;0.05); There was no significant difference in the total number of adverse events between the two groups (P\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e \u003c/em\u003eThe combination of rTMS and amisulpride to enhance olanzapine treatment for TRS has high value. \u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCore Tip:\u003c/strong\u003e rTMS is a widely used treatment method for schizophrenia. This study found that rTMS combined with amisulpride enhanced olanzapine treatment for TRS can significantly improve patients' symptoms, cognitive function, and quality of life, with tolerability and safety.\u003c/p\u003e","manuscriptTitle":"The value of repetitive transcranial magnetic stimulation combined with amisulpride enhancement olanzapine therapy for resistant treatment-refractory schizophrenia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-06 07:14:19","doi":"10.21203/rs.3.rs-7377896/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1acdb834-3e7f-4975-991c-0a42974dc4b9","owner":[],"postedDate":"October 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-03T08:39:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-06 07:14:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7377896","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7377896","identity":"rs-7377896","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}