Publications by authors named "Chih-Sung Liang"

115 Publications

Evidence-Based Expert Consensus Regarding Long-Acting Injectable Antipsychotics for Schizophrenia from the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN).

CNS Drugs 2021 Jul 27. Epub 2021 Jul 27.

Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec 2, Shih-Pai Rd., Beitou, 11217, Taipei, Taiwan.

Objective: Schizophrenia is a chronic, debilitating psychiatric disorder with a high risk of relapse. Nonadherence to medication is a significant contributor to poor outcomes. Although long-acting injectable (LAI) antipsychotics prevent the relapse of schizophrenia, several factors present obstacles to the use of LAI antipsychotics, and clinical guidelines for LAI antipsychotics remain limited. To provide clinical recommendations, the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) developed consensus statements for the effectiveness, target populations, initiation timing, and particular clinical situations for the use of LAI antipsychotics in patients with schizophrenia.

Methods: After a systematic literature review, a working group drafted consensus statements for the selected clinical topics and determined the levels of evidence-based recommendation based on the latest World Federation of Societies of Biological Psychiatry grading system. A scientific committee evaluated the draft statements and decided the final recommendations regarding the grades by anonymous voting after incorporating clinical experience and practice into the evidence from research.

Results: The TSBPN proposed ten consensus statements for the application of LAI antipsychotics. The current evidence supported that LAI antipsychotics could be a treatment option for all schizophrenia patients, including first-episode patients. LAI antipsychotics could be initiated both during an acute psychotic episode and when patients are stable. The consensus also gave recommendations for particular clinical situations with insufficient scientific data, such as for use in elderly or adolescent patients, patients with treatment-resistant schizophrenia, and breakthrough psychosis, and strategies to assist patients/caregivers with decision making.

Conclusions: The consensus statements developed by the TSBPN provide evidence-based clinical recommendations and could give clinicians more confidence when prescribing LAI antipsychotics to treat schizophrenia, thereby improving treatment outcomes.
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http://dx.doi.org/10.1007/s40263-021-00838-5DOI Listing
July 2021

Cancer-related fatigue: light therapy: updated meta-analysis of randomised controlled trials.

BMJ Support Palliat Care 2021 Jul 15. Epub 2021 Jul 15.

Research and Development Division, Health Policy Bureau, Ministry of Health, Labour and Welfare, Tokyo, Japan

Background: Moderate-to-severe cancer-related fatigue occurs in 45% of patients with cancer and interferes with many aspects of quality of life. Although physical exercise has level 1 evidence for improvement of cancer-related fatigue, it has a relatively high behavioural demand compared with other non-pharmacological interventions. The aim of this updated meta-analysis was to address the efficacy of light therapy in improving cancer-related fatigue in patients with cancer.

Methods: We included randomised controlled trials investigating the efficacy of bright white light (BWL) therapy in ameliorating cancer-related fatigue in patients with cancer. This meta-analysis was conducted using a random-effects model. The target outcomes were changes in cancer-related fatigue associated with BWL or dim red light (DRL).

Results: There were 9 articles with 231 participants included. The main results revealed that daily morning BWL for 30 min was associated with significantly better improvement in fatigue severity compared with DRL (=5, Hedges' =-0.414, 95% CI -0.740 to -0.087, p=0.013). The subgroup without psychiatric comorbidities (=4, Hedges' =-0.479, 95% CI -0.801 to -0.156, p=0.004) was associated with significantly better improvement in fatigue severity with BWL than with DRL. In contrary, BWL was not associated with significantly different changes in depression severity or quality of life compared with DRL. Finally, BWL was associated with similar acceptability (ie, dropout rate) and safety profile (ie, any discomfort) as those of DRL.

Conclusions: This meta-analysis provides an updated evidence on the rationale for application of BWL in ameliorating cancer-related fatigue in patients with different types of cancer.

Trial Registration Number: INPLASY202140090.
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http://dx.doi.org/10.1136/bmjspcare-2021-003135DOI Listing
July 2021

The Risk of Alzheimer's Disease After Acute Appendicitis With or Without Appendectomy.

J Am Med Dir Assoc 2021 Jul 13. Epub 2021 Jul 13.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan. Electronic address:

Objective: Previous epidemiologic studies have suggested an association between appendectomy and Parkinson's disease. The aim of the current study was to examine the risk of Alzheimer's disease (AD) and other types of dementia following appendicitis or appendectomy for appendicitis.

Design: Population-based cohort study.

Setting And Participants: We used claims data from the Taiwan National Health Insurance Research Database. Participants aged ≥45 years with acute appendicitis or who received appendectomy for appendicitis were enrolled and followed up for more than 15 years. Cases and controls underwent 1:1 matching by age, sex, index date, and dementia-related comorbidities.

Methods: The primary outcome was AD, and secondary outcomes included other dementia types. Adjusted hazard ratios (aHRs) were calculated, and a competing risk regression model was created. The E value for causality of evidence was calculated.

Results: Patients developing appendicitis (0.6% vs 0.1%, P = .005) and those receiving appendectomy for appendicitis (0.4% vs 0.1%, P = .003) had higher incidences of AD than the controls during the follow-up period. A Cox regression analysis with adjustment for potential confounders showed that patients with appendicitis [aHR 6.68, 95% confidence interval (CI) 1.84-24.48] and those receiving appendectomy for appendicitis (aHR 5.01, 95% CI 1.33-18.85) were more likely to develop AD than the controls. These 2 groups also had higher risks for unspecified dementia and all types of dementia but not for vascular dementia than the controls. The age at dementia diagnosis was 88.51 years in the controls; however, among people who developed dementia following appendicitis, the mean age at diagnosis was 70.18 years, and dementia occurred 5.84 years after appendicitis. The competing risk regression models and the E values support the study findings.

Conclusions And Implications: After recovery from appendicitis, these patients should be followed up for signs of AD.
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http://dx.doi.org/10.1016/j.jamda.2021.06.013DOI Listing
July 2021

Treatment Efficacy and Acceptabilityof Pharmacotherapies for Dementia with Lewy Bodies: A Systematic Review and Network Meta-Analysis.

Arch Gerontol Geriatr 2021 Jul 2;96:104474. Epub 2021 Jul 2.

Institute of Psychiatry, King's College London, UK; Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan. Electronic address:

Introduction: We investigated the efficacy and acceptability of pharmacotherapy for dementia with Lewy bodies (DLB) while simultaneously considering the neuropsychiatric symptoms (NPS), cognitive function, motor symptoms, and acceptability.

Methods: Electronic databases were searched from inception through June 5, 2019, for randomized controlled trials (RCTs) and open-label trials (OLTs) in patients with DLB. We performed a pairwise conventional meta-analysis (PWMA) and network meta-analysis (NMA) within a frequentist framework. The main outcomes were mean change scores in NPS, general cognition, motor symptoms and acceptability. The effect sizes and odds ratios with 95% confidence intervals (CIs) were calculated. This study was registered with PROSPERO (CRD42018096996).

Results: In total, we included 29 studies (9 RCTs and 20 OLTs). In the NMA with 9 RCTs, both high- (mean difference [MD] 2.00, 95% CIs, 0.69 to 3.31) and low-dose (1.86, 0.58 to 3.15) donepezil were associated with a greater cognitive improvement than placebo. High-dose zonisamide was associated with greater motor symptom improvement ( -4.10, -7.03 to -1.17]). No medications reached statistical significance regarding improving neuropsychiatric symptoms or developing intolerable adverse effects as compared to placebo. In the second NMA, with 29 studies as an exploratory analysis, aripiprazole and yokukansan may be effective for neuropsychiatric symptoms, while levodopa may be associated with cognitive impairment.

Conclusions: We report the most comprehensive evidence for the selection of pharmacotherapy for treating different clusters of DLB-related symptoms. Due to the limited availability of RCTs on DLB, more well-conducted RCTs are needed for MMA to warrant clinical efficacy in the future.
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http://dx.doi.org/10.1016/j.archger.2021.104474DOI Listing
July 2021

Better Identification of Cognitive Decline With Interleukin-2 Than With Amyloid and Tau Protein Biomarkers in Amnestic Mild Cognitive Impairment.

Front Aging Neurosci 2021 28;13:670115. Epub 2021 May 28.

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.

The rate of cognitive decline among patients with amnestic mild cognitive impairment (aMCI) varies, and it is thus crucial to accurately predict the probability of cognitive deterioration in patients with MCI. We compared the potential of cytokines with amyloid beta (Aβ) and tau biomarkers for predicting cognitive decline in patients with aMCI or Alzheimer's disease (AD). All participants (controls, aMCI, and AD patients) underwent plasma biomarker examinations for Aβ, Aβ, total tau (t-tau), tau phosphorylated at threonine 181 [-Tau181]), and 29 cytokines and baseline cognitive tests, including Mini-Mental State Examination (MMSE). The correlation between biomarker levels and annual MMSE change during the follow-up was examined. Receiver operating characteristic (ROC) curve analysis was performed to determine whether the statistically significant plasma biomarkers could identify cognitive decline. Higher baseline levels of IL-2, sCD40L, IL-8, and VEGF were associated with a lower annual cognitive decline in the aMCI group, and higher baseline levels of Aβ, IFNγ, IL-5, IL-17A, IL-25, and FGF were associated with a rapid annual cognitive decline in the AD group. IL-2 had a high discriminatory capacity for identifying cognitive decline, with an area under curve (AUC) of 85.7% in the aMCI group, and the AUC was slightly increased when combining IL-2 with Aβ or tau biomarkers. However, none of the biomarkers had a satisfactory discriminatory capacity in the AD group. IL-2 may have a better discriminatory capacity for identifying cognitive decline than Aβ and tau biomarkers in patients with aMCI.
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http://dx.doi.org/10.3389/fnagi.2021.670115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193360PMC
May 2021

The Efficacy of Transcranial Direct Current Stimulation in Enhancing Surgical Skill Acquisition: A Preliminary Meta-Analysis of Randomized Controlled Trials.

Brain Sci 2021 May 27;11(6). Epub 2021 May 27.

Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811, Taiwan.

The application of transcranial direct current stimulation (tDCS) to targeted cortices has been found to improve in skill acquisition; however, these beneficial effects remained unclear in fine and complicated skill. The aim of the current meta-analysis was to investigate the association between tDCS application and the efficacy of surgical performance during surgical skill training. We included randomized controlled trials (RCTs) investigating the efficacy of tDCS in enhancing surgical skill acquisition. This meta-analysis was conducted under a random-effect model. Six RCTs with 198 participants were included. The main result revealed that tDCS was associated with significantly better improvement in surgical performance than the sham control (Hedges' = 0.659, 95% confidence intervals (95%CIs) = 0.383 to 0.935, < 0.001). The subgroups of tDCS over the bilateral prefrontal cortex (Hedges' = 0.900, 95%CIs = 0.419 to 1.382, < 0.001) and the primary motor cortex (Hedges' = 0.599, 95%CIs = 0.245 to 0.953, = 0.001) were both associated with significantly better improvements in surgical performance. The tDCS application was not associated with significant differences in error scores or rates of local discomfort compared with a sham control. This meta-analysis supported the rationale for the tDCS application in surgical training programs to improve surgical skill acquisition.
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http://dx.doi.org/10.3390/brainsci11060707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229080PMC
May 2021

APOE Allele Testing and Alzheimer Disease.

JAMA 2021 06;325(21):2210-2211

Beitou Branch, Tri-Service General Hospital, Taipei, Taiwan.

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http://dx.doi.org/10.1001/jama.2021.4919DOI Listing
June 2021

Efficacy of serotonergic antidepressant treatment for the neuropsychiatric symptoms and agitation in dementia: A systematic review and meta-analysis.

Ageing Res Rev 2021 08 14;69:101362. Epub 2021 May 14.

Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Non-invasive Neuromodulation Consortium for Mental Disorders, Society of Psychophysiology, Taipei, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Objective: Serotonergic dysfunction may be involved in the etiology of overall neuropsychiatric symptoms (NPS) and agitation in patients with dementia; therefore, we aim to perform a systematic review and meta-analysis to investigate the efficacy of serotonergic antidepressants in such populations.

Methods: We systematically searched PubMed, Medline, Embase, and Cochrane Library to obtain randomized controlled trials (RCTs) from the date of their inception until December 11, 2020 to examine the effect of serotonergic antidepressants on the outcomes of interest in patients with dementia. Data were pooled using a random-effects model. Co-primary outcomes were mean changes in overall NPS and agitation as a specific symptom of NPS. Secondary outcomes were mean changes in depressive symptoms, cognition, and care burden.

Results: Fourteen randomized controlled trials were eligible (n = 1,374; mean age = 76.8 years; mean proportion of female = 61.9 %). Serotonergic antidepressants significantly reduced the overall NPS (k = 12, n = 1276, Hedges' g = -0.49, 95 % confidence intervals [CIs] = -0.74 to -0.24, p < 0.001) and agitation severity (k = 9, n = 749, Hedges' g = -0.28, 95 % CIs = -0.43 to -0.14, p < 0.001), both with small effect size in patients with dementia. For secondary outcome, serotonergic antidepressants also significantly improved depressive symptoms, cognition, and care burden with small to very small effect sizes (depressive symptoms, k = 8, n = 938, Hedges' g = -0.32, 95 % CIs = -0.49 to -0.15, p < 0.001;cognition, k = 6, n = 983, Hedges' g = 0.15, 95 % CIs = 0.002 to 0.29, p = 0.046; care burden, k = 7, n = 961, Hedges' g = -0.24, 95 % CIs = -0.41 to -0.07, p = 0.005). Subgroup analysis showed that both selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs significant reduced agitation and depressive symptoms (For agitation, SSRIs, k = 6, n = 605, Hedges' g = -0.25, 95 % CIs = -0.41 to -0.09, p=0.002; non-SSRIs, k = 3, n = 144, Hedges' g = -0.41, 95 % CIs = -0.74 to -0.08, p = 0.016; For depression, SSRIs, k = 6, n = 736, Hedges' g = -0.29, 95 % CIs = -0.48 to -0.09, p=0.004; non-SSRIs, k = 343, n = 144, Hedges' g = -0.43, 95 % CIs = -0.78 to -0.09, p = 0.016), whereas only SSRIs reduced overall NPS (k = 9, n = 1109, Hedges' g = -0.49, 95 % CIs = -0.78 to -0.20, p = 0.001) and care burden (k = 5, n = 740, Hedges' g = -0.29, 95 % CIs = -0.50 to -0.08, p=0.007).

Conclusion: The present meta-analysis indicates that serotonergic antidepressants effectively alleviate overall NPS, agitation, depressive symptoms, and care burden, and improve cognitive function.
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http://dx.doi.org/10.1016/j.arr.2021.101362DOI Listing
August 2021

Efficacy and acceptability of noninvasive brain stimulation interventions for weight reduction in obesity: a pilot network meta-analysis.

Int J Obes (Lond) 2021 Aug 10;45(8):1705-1716. Epub 2021 May 10.

Division of Community & Rehabilitation Psychiatry, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.

Background/objectives: Obesity has recently been recognized as a neurocognitive disorder involving circuits associated with the reward system and the dorsolateral prefrontal cortex (DLPFC). Noninvasive brain stimulation (NIBS) has been proposed as a strategy for the management of obesity. However, the results have been inconclusive. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and acceptability of different NIBS modalities for weight reduction in participants with obesity.

Methods: Randomized controlled trials (RCTs) examining NIBS interventions in patients with obesity were analyzed using the frequentist model of NMA. The coprimary outcome was change in body mass index (BMI) and acceptability, which was calculated using the dropout rate.

Results: Overall, the current NMA, consisting of eight RCTs, revealed that the high-frequency repetitive transcranial magnetic stimulation (TMS) over the left DLPFC was ranked to be associated with the second-largest decrease in BMI and the largest decrease in total energy intake and craving severity, whereas the high-frequency deep TMS over bilateral DLPFC and the insula was ranked to be associated with the largest decrease in BMI.

Conclusion: This pilot study provided a "signal" for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on weight reduction in participants with obesity by different NIBS interventions.
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http://dx.doi.org/10.1038/s41366-021-00833-2DOI Listing
August 2021

Month of birth and mental disorders: A population-based study and validation using global meta-analysis.

Acta Psychiatr Scand 2021 Aug 18;144(2):153-167. Epub 2021 May 18.

Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan.

Objective: Month of birth (MOB) is associated with specified mental disorders (MDs). However, whether these relationships extend to all MDs remains unclear. We investigate the association using a population-based cohort study and a meta-analysis.

Methods: First, we examined patients with 34 DSM-5-classified MDs in the Taiwan national database. We estimated the relative risk ratios (RR) of each illness in each MOB relative to that in the general population and assessed the periodicity, with six further sensitivity analyses. Second, we searched PubMed, Embase, and Cochrane for related articles through 31 December 2020. We used a random-effects model, pooled RRs with 95% confidence intervals of each MOB from the identified studies, and transformed them from MOB to relative age in a year or season.

Results: The cohort included 1,951,777 patients. Except for posttraumatic stress disorder, dissociative disorders, feeding/eating disorders, gender dysphoria, and paraphilic disorders, the other MDs had significant MOB periodicity. The meta-analysis included 51 studies investigating 10 MDs. The youngest age at the start of school owing to MOB was associated with the highest RRs of intellectual disability (1.13), autism (1.05), attention-deficit/hyperactivity disorder (1.13). Winter births had significant risks of schizophrenia (1.04), bipolar I disorder (1.02), and major depressive disorder (1.01), and autumn births had a significant risk of alcohol use disorder (1.02). No significant associations between season of birth and Alzheimer's disease, or eating disorders were found.

Conclusions: MOB is related to the risks of certain MDs. This finding provides a reference for future research on the etiology of MDs.
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http://dx.doi.org/10.1111/acps.13313DOI Listing
August 2021

Risks of Major Mental Disorders and Irritable Bowel Syndrome among the Offspring of Parents with Irritable Bowel Syndrome: A Nationwide Study.

Int J Environ Res Public Health 2021 04 28;18(9). Epub 2021 Apr 28.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112, Taiwan.

Irritable bowel syndrome (IBS) is a functional bowel disorder that is highly comorbid with mental disorders. However, few studies have examined the risk of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), and schizophrenia in the offspring of parents with IBS. We used nationally representative cross-sectional survey data to analyze cross-generational transmission patterns of both IBS and major mental disorders. Odds ratio (OR) was calculated by using logistic regression models with adjustment for potential confounding factors. Offspring of parents with IBS were more likely to develop IBS themselves (OR = 2.41, 95% confidence interval (CI), 2.09-2.78), ADHD (OR = 1.33, 95% CI, 1.08-1.62), and MDD (OR = 1.32, 95% CI, 1.04-1.68) than the controls. Data stratification by parental sex revealed that paternal IBS increased risk of ADHD (OR = 1.34, 95% CI, 1.01-1.77) in the offspring, while maternal IBS increased the risk of MDD (OR = 1.51, 95% CI, 1.11-2.06). This is the first study to reveal parental IBS is associated with IBS, ADHD, and MDD among offspring, suggesting the necessity for early implementation of prevention strategies for at-risk children.
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http://dx.doi.org/10.3390/ijerph18094679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124475PMC
April 2021

Efficacy and acceptability of different anti-fungal interventions in oropharyngeal or esophageal candidiasis in HIV co-infected adults: a pilot network meta-analysis.

Expert Rev Anti Infect Ther 2021 May 16:1-11. Epub 2021 May 16.

Program in Translational Medicine, National Chung Hsing University, Taichung City, Taiwan.

: Oropharyngeal/esophageal candidiasis are the most common opportunistic infections observed in patients with human immunodeficiency virus (HIV). While the commonly recommended treatment is fluconazole, relapse of oropharyngeal or esophageal candidiasis has been gradually increasing in recent decades.: The current network meta-analysis (NMA) included randomized controlled trials (RCTs) investigating the efficacy and acceptability (i.e. drop-out rate) of different anti-fungal interventions against oropharyngeal or esophageal candidiasis in adults with HIV. All NMA procedures were conducted using the frequentist model.: Twenty-seven RCTs and 6277 participants were included. For oropharyngeal candidiasis, photosensitizer-based antimicrobial photodynamic therapy (aPDT) with laser irradiation plus methylene blue was associated with the highest cure rate and the lowest relapse rate among the investigated interventions [odds ratio (OR) = 6.82, 95% confidence intervals (95%CIs) = 0.19 to 244.42, p = 0.293, and OR = 0.03, 95%CIs = 0.00 to 0.77, p = 0.034, compared to fluconazole]. None of the investigated anti-fungal interventions were superior to fluconazole for esophageal candidiasis in respect of cure rates/relapse rates. All investigated anti-fungal interventions were well-accepted.: aPDT could be the preferred strategy to manage oropharyngeal candidiasis; however the evidence for esophageal candidiasis still remained inconclusive.
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http://dx.doi.org/10.1080/14787210.2021.1922078DOI Listing
May 2021

Response Letter Regarding the "Questions About the Results Described in the Article: The Efficacy and Safety of Tube Feeding in Advanced Dementia Patients: A Systemic Review and Meta-Analysis Study".

J Am Med Dir Assoc 2021 Jul 15;22(7):1561-1562. Epub 2021 Apr 15.

Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Center for Geriatrics and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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http://dx.doi.org/10.1016/j.jamda.2021.02.024DOI Listing
July 2021

Prevalence and association of lifestyle and medical-, psychiatric-, and pain-related comorbidities in patients with migraine: A cross-sectional study.

Headache 2021 May 5;61(5):715-726. Epub 2021 Apr 5.

Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background And Objectives: Migraine has been associated with many comorbidities. However, lifestyle factors and the presence of comorbid diseases have not previously been extensively studied in the same sample. This study aimed to compare the prevalence of unhealthy lifestyle factors and comorbid diseases between patients with migraine and migraine-free controls with subgroup analyses to determine the pathophysiology and possible consequences.

Methods: This cross-sectional study recruited 1257 patients with migraine between the ages of 20 and 65 years from a headache outpatient clinic in Taiwan and 496 non-migraine controls. All participants completed questionnaires regarding demographics, migraine diagnosis, sleep, headache burden, and medical, pain, and psychiatric conditions. Participants also underwent a structured interview. The associations between comorbidities and migraine were investigated and further stratified by sex and aura.

Results: Patients with migraine with aura had an unhealthier lifestyle compared with controls in the form of current smoking status (15.5% [67/431] vs. 11.5% [57/496], p = 0.013). Furthermore, medical- (e.g., thyroid disease; 7.2% [91/1257 vs. 2.8% [14/496]; p = 0.006), psychiatric- (e.g., depression; 6% [76/1257 vs. 2.6% [13/496]; p = 0.031), and pain-related (e.g., fibromyalgia; 8% [101/1257 vs. 3.2% [16/496]; p = 0.006) comorbidities were more prevalent in patients compared with controls. Subgroup analyses revealed that chronic migraine, migraine with aura, and female sex were associated with a greater number of significant comorbidities than episodic migraine, migraine without aura, and male patients with migraine, respectively.

Conclusion: Individuals seeking treatment for migraine reported greater levels of smoking and medical, psychiatric, and pain conditions than non-treatment-seeking healthy controls who were recruited from the community. Understanding the relationship between migraine and comorbid diseases may improve medical care as well as the quality of life.
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http://dx.doi.org/10.1111/head.14106DOI Listing
May 2021

Driving Impairment Following Vaporization of Cannabis.

JAMA 2021 03;325(12):1225-1226

Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

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http://dx.doi.org/10.1001/jama.2021.0448DOI Listing
March 2021

The Risk of Epilepsy after Long-term Proton Pump Inhibitor Therapy.

Seizure 2021 Apr 11;87:88-93. Epub 2021 Mar 11.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address:

Background: Prescription-event monitoring studies have reported incident epilepsy or seizures in proton pump inhibitor (PPI) recipients. We examined the risk of epilepsy after prolonged PPI exposure and determine what age group was at higher risk of epilepsy.

Methods: We performed a case-control study nested within a sample of Taiwan National Health Insurance beneficiaries (n = 1,000,000). PPI users with subsequent epilepsy were selected as the case cohort. Controls were PPI users without subsequent epilepsy, matched for age, sex, PPI use indication, enrollment time, end point time, follow-up period, overall systemic health, and comorbidities. The total dose of PPI was defined as the cumulative defined daily dose (cDDD). Prolonged PPI use was defined as a cDDD > 365. A logistic regression analysis was performed. Population attributable risk was calculated.

Results: Epilepsy occurred 4.13 years after the initiation of PPI use. PPI users with the highest risk of incident epilepsy received a cDDD > 365 [odds ratio = 1.63, 95% confidence interval = 1.37-1.95], followed by 121-365 cDDD (1.33, 1.18-1.51) and 31-120 cDDD (1.15, 1.02-1.29), compared to those receiving a cDDD ≤ 30, after adjusting for potential confounders. Prolonged PPI use increased the risk of epilepsy in all age groups, and the risk was highest for those older than 80 years (3.11, 1.67-5.79). The population attributable risk was 12.2% (> 365 cDDD vs ≤ 30 cDDD).

Discussion: Prolonged PPI therapy was associated with an increased risk of epilepsy, particularly in the elderly population.
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http://dx.doi.org/10.1016/j.seizure.2021.03.008DOI Listing
April 2021

Atopic dermatitis and dementia risk: A nationwide longitudinal study.

Ann Allergy Asthma Immunol 2021 Mar 11. Epub 2021 Mar 11.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address:

Background: Retrospective studies have suggested that patients with dementia have higher prevalence of atopic dermatitis (AD) than those without dementia. However, the temporal association of AD with subsequent dementia remains unknown.

Objective: To assess the temporal association of AD with subsequent dementia.

Methods: We included data of patients with AD aged 45 years and older (n = 1059) and 1:10 age, sex, residence, income, and dementia-related comorbidity-matched controls (n = 10,590) from the Taiwan National Health Insurance Research Database and reviewed their subsequent dementia development from the enrollment date to the end of 2013.

Results: After adjustments for dementia-related comorbidities, patients with AD were found to be more likely to develop any dementia (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.24-3.29), particularly Alzheimer's disease (HR, 3.74; 95% CI, 1.17-11.97), during the follow-up period than those in the control group. Moderate-to-severe AD was associated with a high subsequent dementia risk (HR, 4.64; 95% CI, 2.58-8.33). Sensitivity analyses with the exclusion of the first 3 (HR, 2.20; 95% CI, 1.28-3.80) or 5 (HR, 2.05; 95% CI, 1.08-3.89) years of observation revealed consistent findings.

Conclusion: AD may be an independent risk factor for new-onset dementia. Clinicians may monitor the trajectory of neurocognitive function among elderly patients with AD. Additional studies elucidating the pathomechanisms between AD and subsequent dementia are warranted.
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http://dx.doi.org/10.1016/j.anai.2021.03.001DOI Listing
March 2021

Disentangling the complex bidirectional associations between COVID-19 and psychiatric disorder.

Lancet Psychiatry 2021 03;8(3):179

Department of Psychiatry, Beitou Branch, National Defense Medical Center, Taipei 112, Taiwan; Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/S2215-0366(20)30565-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906693PMC
March 2021

Therapeutic benefits of pharmacologic and nonpharmacologic treatments for depressive symptoms after traumatic brain injury: a systematic review and network meta-analysis.

J Psychiatry Neurosci 2021 01 21;46(1):E196-E207. Epub 2021 Jan 21.

From the Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Kaohsiung, Taiwan (Cheng, Wu); the Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung City, Taiwan (Cheng, Tseng); the WinShine Clinics in Specialty of Psychiatry, Kaohsiung, Taiwan (Tseng); the Prospect Clinic for Otorhinolaryngology & Neurology (Tseng, Chen); the Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan (Wu); the Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (Tu); the Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan (Hsu, Wu, Lin); the Division of Allergy, Immunology, Rheumatology Disease, Department of Pediatrics, Mackay Memorial Hospital, Hsinchu, Taiwan (Lei); the Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Lei Taiwan (Li); the Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan (Li); the Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan (Chen); the Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan (Chen); the Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK (Stubbs); Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, UK (Stubbs); the Department of Psychiatry, University of Toronto, Toronto, ON (Carvalho); the Centre for Addiction & Mental Health (CAMH), Toronto, ON (Carvalho); the Department of Psychiatry, Beitou branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan (Liang); the Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan (Liang); the Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan (Yeh); the Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan (Chu); the Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Chu); the Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (Lin); the Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan (Wu); the Department of Emergency Medicine, E-Da Hospital, Kaohsiung, Taiwan (Sun); the I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (Sun).

Background: Depression is a common morbidity after traumatic brain injury. This network meta-analysis investigated the efficacy and tolerability of pharmacologic and nonpharmacologic interventions for depression after traumatic brain injury.

Methods: We extracted randomized controlled trials examining pharmacologic or nonpharmacologic interventions with placebo- or active-controlled designs from PubMed, the Cochrane Library and ScienceDirect, from inception to October 30, 2018. We based study selection and extraction of a predefined list of variables on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, and conducted meta-analysis procedures using random effects modelling. Primary outcomes were changes in depressive symptom severity after pharmacologic or nonpharmacologic treatment; the secondary outcome was tolerability, reflected in overall patient dropout rates.

Results: Our analysis of 27 randomized controlled trials (10 pharmacologic, total n = 483, mean age = 37.9 yr; 17 nonpharmacologic, total n = 1083, mean age = 38.0 yr) showed that methylphenidate had significantly superior efficacy compared to placebo or control (standardized mean difference -0.91, 95% confidence interval [CI] -1.49 to -0.33). Sertraline was associated with significantly lower tolerability (i.e., a higher dropout rate) compared to placebo or control (odds ratio 2.65, 95% CI 1.27 to 5.54). No nonpharmacologic treatment was more effective than the others, and we found no significant differences in tolerability (i.e., dropout rates) among the nonpharmacologic treatments.

Limitations: Heterogeneity in participant characteristics (e.g., comorbidities), study designs (e.g., trial duration) and psychopathology assessment tools, as well as small trial numbers for some treatment arms, could have been confounders.

Conclusion: The present network meta-analysis suggests that methylphenidate might be the best pharmacologic intervention for depressive symptoms related to traumatic brain injury. None of the nonpharmacologic interventions was associated with better improvement in depressive symptoms than the others or than control conditions. None of the pharmacologic or nonpharmacologic treatments had inferior tolerability compared to placebo or controls except for sertraline, which had significantly lower tolerability than placebo.
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http://dx.doi.org/10.1503/jpn.190122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955847PMC
January 2021

Risk of Substance Use Disorder and Its Associations With Comorbidities and Psychotropic Agents in Patients With Autism.

JAMA Pediatr 2021 Feb 1;175(2):e205371. Epub 2021 Feb 1.

Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Importance: The risk of substance use disorder (SUD) in patients with autism spectrum disorder (ASD) remains unclear.

Objective: To investigate the risk of SUD in patients with ASD and its associations with comorbidities, psychotropic agents (PAs), and mortality.

Design, Setting, And Participants: This retrospective, population-based, cohort study of 1 936 512 participants used data from the Taiwan National Health Insurance Research Database and was conducted from January 1, 2000, to December 31, 2015. Included participants attended at least 3 outpatient visits within the 1-year study period for symptomatic ASD as determined by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes. Individuals diagnosed with ASD before 2000, those diagnosed with SUD before the first visit for ASD, and those with missing data were excluded from the analysis. Patients with ASD and non-ASD controls were matched 1:4 by age, sex, and index date.

Exposures: Symptomatic ASD evaluated for at least 3 outpatient visits within the 1-year study period.

Main Outcomes And Measures: Adjusted hazard ratios (aHRs) with 95% CIs for SUD, including alcohol use disorder (AUD) and drug use disorder (DUD), and the risk of mortality were calculated. Data were analyzed from March 1 to July 13, 2020.

Results: A total of 6599 individuals with ASD (mean [SD] age, 11.9 [5.1] years; 5094 boys [77.2%]; mean [SD] follow-up period, 8.1 [8.3] years; median follow-up period, 4.3 [interquartile range [IQR], 2.3-5.3] years) and 26 396 controls (mean [SD] age, 12.1 [5.8] years; 20 376 boys [77.2%]; mean [SD] follow-up period, 8.6 [8.9] years; median follow-up period, 4.4 [IQR, 2.4-5.4] years) were enrolled in the study. According to multivariable-adjusted analysis, the aHRs for SUD (2.33; 95% CI, 1.89-2.87), AUD (2.07; 95% CI, 1.60-2.63), and DUD (3.00; 95% CI, 2.15-4.58) were significantly higher in the ASD group than in the non-ASD controls. The aHRs for SUD in the ASD subgroups with 1 PA (0.60; 95% CI, 0.43-0.66) and with multiple PAs (0.37; 95% CI, 0.28-0.49) were significantly lower than those in the ASD subgroup with no PAs. Comparisons between patients with ASD and non-ASD controls with the same comorbidities showed higher aHRs for SUD among patients with ASD (range, 1.17-2.55); moreover, the ASD subgroup not receiving any PAs had an aHR of 6.39 (95% CI, 5.11-7.87) for SUD when they had comorbid tic disorder and aHRs of 5.48 (95% CI, 5.12-5.70) for AUD and 5.42 (95% CI, 5.12-5.80) for DUD when they had comorbid impulse control disorder. The mortality risk was significantly higher in patients with ASD and concomitant SUD than in non-ASD controls without SUD (aHR, 3.17; 95% CI, 2.69-3.89).

Conclusions And Relevance: These findings suggest that patients with ASD are vulnerable to the development of SUD. Comorbid ASD and SUD were associated with an increase in mortality risk.
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http://dx.doi.org/10.1001/jamapediatrics.2020.5371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783585PMC
February 2021

Incongruent Expression of Brain-Derived Neurotrophic Factor and Cortisol in Schizophrenia: Results from a Randomized Controlled Trial of Laughter Intervention.

Psychiatry Investig 2020 Dec 11. Epub 2020 Dec 11.

Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.

Objective: Schizophrenia has been associated with dysfunction of the hypothalamic-pituitary-adrenal axis. Furthermore, alterations in neurotrophic factors might contribute to the pathogenesis of schizophrenia. We aimed to evaluate the effects of a simulated laughter intervention on the levels of cortisol and BDNF and to determine whether the effects associated with simulated laughter could be sustained after discontinuation of the intervention.

Methods: In this randomized controlled study, patients with schizophrenia according to DSM-IV clinical criteria were randomly assigned to receive either 8-week-long simulated laughter intervention (n=32) or treatment-as-usual group (control group, n=27). The serum levels of BDNF and cortisol were measured at baseline, week 8, and four weeks after discontinuation (week 12) of the intervention program.

Results: After an 8-week simulated laughter intervention, the laughter group had significantly higher levels of BDNF; however, four weeks after discontinuation of the intervention, the levels of BDNF significantly dropped. Interestingly, the levels of cortisol did not change significantly at week 8, but they were significantly elevated at week 12. The levels of BDNF and cortisol in the control group did not change significantly between week 0 and week 8.

Conclusion: These findings suggest that the simulated laughter intervention has an early effect on neurogenesis with a significant delayed effect on stress regulation in subjects with schizophrenia.
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http://dx.doi.org/10.30773/pi.2020.0269DOI Listing
December 2020

Efficacy and tolerability of theta-burst stimulation for major depression: A systematic review and meta-analysis.

Prog Neuropsychopharmacol Biol Psychiatry 2021 03 7;106:110168. Epub 2020 Nov 7.

Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Cognitive Neuroscience, National Central University, Jhongli, Taiwan; Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Brain Science and Brain Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Background: Repetitive transcranial magnetic stimulation (rTMS) is the current treatment option for major depression (MD). Theta-burst stimulation (TBS), a variation of rTMS, affords a short stimulation duration, low stimulation pulse intensity, and possibility to improve rTMS efficiency. This systematic review and meta-analysis examined the studies on efficacy and tolerability of TBS in patients with MD.

Methods: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the literature from 1990 until May 24, 2020, and performed a random-effects meta-analysis by including response and remission rates of depression and dropout rates as main outcome measures.

Results: In total, 10 studies including 6 randomized controlled trials (RCTs; n = 294) and 4 uncontrolled clinical trials (non-RCTs; n = 297) were included. The overall effect size of response rate and remission rates were 0.38 (95% confidence interval [CI]: 0.29-0.48) and 0.20 (95% CI: 0.13-0.29), respectively. Notably, the TBS group showed favorable efficacy without major adverse events.

Conclusions: TBS treatment was more efficient in terms of time and energy than the standard rTMS was. Our meta-analysis provided evidence that the application of TBS to the dorsolateral prefrontal cortex is associated with significant antidepressant effects along with favorable tolerability.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110168DOI Listing
March 2021

Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimer's disease and mild cognitive impairment: a component network meta-analysis.

J Neurol Neurosurg Psychiatry 2021 02 28;92(2):195-203. Epub 2020 Oct 28.

Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, Taipei, Taiwan

Objectives: To compare cognitive effects and acceptability of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI), and to determine whether cognitive training (CT) during rTMS or tDCS provides additional benefits.

Methods: Electronic search of PubMed, Medline, Embase, the Cochrane Library and PsycINFO up to 5 March 2020. We enrolled double-blind, randomised controlled trials (RCTs). The primary outcomes were acceptability and pre-post treatment changes in general cognition measured by Mini-Mental State Examination, and the secondary outcomes were memory function, verbal fluency, working memory and executive function. Durability of cognitive benefits (1, 2 and ≥3 months) after brain stimulation was examined.

Results: We included 27 RCTs (n=1070), and the treatment components included high-frequency rTMS (HFrTMS) and low-frequency rTMS, anodal tDCS (atDCS) and cathodal tDCS (ctDCS), CT, sham CT and sham brain stimulation. Risk of bias of evidence in each domain was low (range: 0%-11.1%). HFrTMS (1.08, 9, 0.35-1.80) and atDCS (0.56, 0.03-1.09) had short-term positive effects on general cognition. CT might be associated with negative effects on general cognition (-0.79, -2.06 to 0.48) during rTMS or tDCS. At 1-month follow-up, HFrTMS (1.65, 0.77-2.54) and ctDCS (2.57, 0.20-4.95) exhibited larger therapeutic responses. Separate analysis of populations with pure AD and MCI revealed positive effects only in individuals with AD. rTMS and tDCS were well tolerated.

Conclusions: HFrTMS is more effective than atDCS for improving global cognition, and patients with AD may have better responses to rTMS and tDCS than MCI.
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http://dx.doi.org/10.1136/jnnp-2020-323870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841477PMC
February 2021

Identifying neuroanatomical signatures in insomnia and migraine comorbidity.

Sleep 2021 03;44(3)

Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Study Objectives: While insomnia and migraine are often comorbid, the shared and distinct neuroanatomical substrates underlying these disorders and the brain structures associated with the comorbidity are unknown. We aimed to identify patterns of neuroanatomical substrate alterations associated with migraine and insomnia comorbidity.

Methods: High-resolution T1-weighted images were acquired from subjects with insomnia, migraine, and comorbid migraine and insomnia, respectively, and healthy controls (HC). Direct group comparisons with HC followed by conjunction analyses identified shared regional gray matter volume (GMV) alterations between the disorders. To further examine large-scale anatomical network changes, a seed-based structural covariance network (SCN) analysis was applied. Conjunction analyses also identified common SCN alterations in two disease groups, and we further evaluated these shared regional and global neuroanatomical signatures in the comorbid group.

Results: Compared with controls, patients with migraine and insomnia showed GMV changes in the cerebellum and the lingual, precentral, and postcentral gyri (PCG). The bilateral PCG were common GMV alteration sites in both groups, with decreased structural covariance integrity observed in the cerebellum. In patients with comorbid migraine and insomnia, shared regional GMV and global SCN changes were consistently observed. The GMV of the right PCG also correlated with sleep quality in these patients.

Conclusion: These findings highlight the specific role of the PCG in the shared pathophysiology of insomnia and migraine from a regional and global brain network perspective. These multilevel neuroanatomical changes could be used as potential image markers to decipher the comorbidity of the two disorders.
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http://dx.doi.org/10.1093/sleep/zsaa202DOI Listing
March 2021

Association of genetic variants in migraineurs with and without restless legs syndrome.

Ann Clin Transl Neurol 2020 10 12;7(10):1942-1950. Epub 2020 Sep 12.

Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Objective: Several single-nucleotide polymorphisms (SNPs) are associated with restless legs syndrome (RLS). This study investigated whether or not additional SNP variants increase the risk of RLS in migraineurs and in migraine with aura (MA) and migraine without aura (MoA) subgroups.

Methods: Migraineurs with and without RLS were genotyped using an Affymetrix array. We performed association analyses for the entire cohort and the MA and MoA subgroups, which were divided further into episodic migraine (EM) and chronic migraine (CM). Potential correlations between SNPs and clinical indices in migraineurs with RLS were examined by multivariate regression analysis.

Results: The rs77234324 and rs79004933 SNPs were found in migraineurs with (P = 2.57E-07) and without (P = 3.03E-07) RLS. The A allele frequency for rs77234324 (on LGR6) was 0.1321 in migraineurs with RLS and 0.0166 in those without RLS (odds ratio, 8.978). The T allele frequency for rs79004933 (in the intergenic region) was 0.1981 in migraineurs with RLS and 0.0446 in those without (odds ratio, 5.281). rs2858654, rs76770509, rs4243475 in UTRN, rs150762626, and rs2668375 were identified in migraine with and without RLS in the MoA subgroup (P = 7.56E-09, P = 2.30E-08, P = 1.19E-07, P = 6.86E-07, and P = 8.05E-07, respectively). There was a suggestion of an association between rs10510331 (P = 1.50E-06) and CM and EM in patients with MoA and RLS. Multivariate regression showed a significant relationship between rs79004933 and the Beck Depression Inventory score.

Interpretation: rs77234324 in LGR6 and rs79004933 in the intergenic region were associated with RLS in migraineurs. Five SNPs increased the risk of RLS in patients with MoA.
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http://dx.doi.org/10.1002/acn3.51186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545615PMC
October 2020

Female reproductive health and cognitive function.

Menopause 2020 12;27(12):1357-1362

Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Objective: The impact of sex hormones milieu on women's cognitive performance at different reproductive stages has caused increased caution. Our research aims to explore whether parity is negatively correlated with cognitive function.

Methods: There were 1,093 postmenopausal participants recruited from the Health and Nutrition Examination Survey dataset. Cognitive functioning was evaluated by digit symbol substitution test (DSST). We performed log transformation to normalize the distributions of the DSST values.

Results: Participants were categorized into tertile groups based on the number of pregnancies. Using the zero to one pregnancy group as the reference, there was a reduced DSST scores with β values of -0.13 (95% confidence interval [CI] -0.23 to -0.03; P = 0.008) in the ≥5 pregnancies group after adjusting for socioeconomic, medical disease, lifestyle, and reproductive components. Moreover, women who had their last pregnancy after 28 years old and education less than 12 years also was correlate with cognitive malfunction after adjusting relevant covariates (both P < 0.001).

Conclusions: Women with at least five pregnancies had poorer cognitive performance. Last pregnancy after 28 years old and education less than 12 years also was associated with poorer DSST scores. VIDEO SUMMARY:: http://links.lww.com/MENO/A634.
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http://dx.doi.org/10.1097/GME.0000000000001630DOI Listing
December 2020

The Efficacy and Safety of Tube Feeding in Advanced Dementia Patients: A Systemic Review and Meta-Analysis Study.

J Am Med Dir Assoc 2021 02 29;22(2):357-363. Epub 2020 Jul 29.

Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Center for Geriatrics and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Non-invasive Neuromodulation Consortium for Mental Disorders, Society of Psychophysiology, Taipei, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Objectives: The current study aimed to conduct a systematic review and meta-analysis to explore the efficacy and safety of tube feeding in patients with advanced dementia.

Design: Systematic review and meta-analysis.

Setting And Participants: PubMed, Medline, Embase, and Cochrane Library were searched from inception until March 7, 2020, to obtain relevant studies.

Intervention: Feeding with nasogastric tube or percutaneous endoscopic gastrostomy (PEG).

Measures: We evaluated the associations of tube feeding and the risk of mortality, period of survival days, tube-related complications, and nutritional status. Data from original studies were synthesized by using a random-effects model. Each selected article was assessed for bias using the Newcastle-Ottawa Scale. A narrative synthesis and pooled analyses are reported.

Results: Twelve trials were eligible, involving 1805 patients with tube feeding (mean age: 82.8 years; 71.3% female) and 3861 without tube feeding (mean age: 82.7; 68.7% female). For mortality rate, patients with advanced dementia with tube feeding are associated with significantly higher mortality rate [k = 8; odds ratio (OR) 1.79; 95% confidence interval (CI) 1.04-3.07; P = .03]. Initially, no association was found for the risk of pneumonia and pressure sore between groups. However, sensitivity analysis showed patients with advanced dementia with PEG tube feeding have significantly higher risk of pneumonia (OR 3.56; 95% CI 2.32-5.44; P < .001) and pressure sore (OR 2.25; 95% CI 1.92-2.63; P < .001). Finally, no association was found for the survival period and nutritional status between groups.

Conclusions And Implications: This meta-analysis indicates that tube feeding is associated with increased mortality rate and possible tube-related complications, but not improves with prolonging survival days and nutritional status. Shared decision-making routinely before insertion of a tube between caregivers and physicians is recommended.
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http://dx.doi.org/10.1016/j.jamda.2020.06.035DOI Listing
February 2021

Tinnitus and risk of Alzheimer's and Parkinson's disease: a retrospective nationwide population-based cohort study.

Sci Rep 2020 07 22;10(1):12134. Epub 2020 Jul 22.

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Tinnitus has been implied as a "soft" sign of neurodegenerative disease, which is characterized by progressive loss of neuronal function, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aimed to determine whether the risk of developing AD/PD increases after having tinnitus. We conducted a retrospective matched cohort study with 12,657 tinnitus patients and 25,314 controls from the National Health Insurance Research Database (NHIRD) in Taiwan with almost 10 years follow-up. Tinnitus-related risk on developing AD/PD followingly was determined by the Cox regression to identify potential confounding factors. Through the 10-year follow-up period, 398 individuals with tinnitus (3.1%) and 501 control individuals (2.0%) developed AD (P < 0.001), and 211 tinnitus patients (1.7%) and 249 control patients (1.0%) developed PD (P < 0.001). Compared with controls, patients with tinnitus were 1.54 times more likely to develop AD (95% confidence interval (CI) 1.34-1.78, P < 0.001) and 1.56 times more likely to develop PD (95% CI 1.29-1.89, P < 0.001), after adjusting confounding factors. Our results indicate an association between tinnitus and higher risk of developing AD and PD. Additional physical comorbidities may also increase the risk of developing AD and PD.
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http://dx.doi.org/10.1038/s41598-020-69243-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376045PMC
July 2020

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer's disease.

Alzheimers Res Ther 2020 07 16;12(1):86. Epub 2020 Jul 16.

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.

Background: The neuroprotective role of interleukin (IL)-33 is supported by numerous preclinical studies, but it remains uninvestigated in clinical studies of Alzheimer's disease (AD). We aimed to examine the association between human blood levels of IL-33 and cognitive preservation in amnestic mild cognitive impairment (aMCI) and AD.

Methods: A total of 100 participants (26 controls, 35 aMCI patients, and 39 AD patients) completed two Mini-Mental State Examinations (MMSEs) over a 1-year interval. In all 100 participants at the second MMSE, we examined the plasma levels of IL-33, IL-β, IL-1 receptor agonist (IL-1RA), beta amyloid (Aβ), and tau and apolipoprotein E (ApoE) genotyping; we also performed Hopkins Verbal Learning Test, Trail Making Test, forward and backward digit span, and Clinical Dementia Rating.

Results: IL-33 expression showed a positive trend among controls (1/26 = 3.8%), aMCI (9/35 = 25.7%), and AD (17/39 = 43.6%) (trend analysis: P < 0.001). Patients expressing IL-33 preserved their cognitive function compared with IL-33 non-expressing patients (1-year ΔMMSE, 0.16 ± 1.6 vs - 1.5 ± 2.6; P = 0.006). The cognitive preservation was not associated with the lower levels of Aβ, tau, and ApoE ε4, while higher levels of ApoE ε4 and phosphorylated tau were indeed associated with cognitive decline. The aMCI patients with AD conversion during study period had higher proportion of IL-33(-) than non-AD converters (90.9% vs 53.3%, P = 0.04).

Conclusions: IL-33 or its associated signaling pathways may represent a new treatment paradigm for aMCI and AD.
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http://dx.doi.org/10.1186/s13195-020-00652-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367330PMC
July 2020

Association of Central Noninvasive Brain Stimulation Interventions With Efficacy and Safety in Tinnitus Management: A Meta-analysis.

JAMA Otolaryngol Head Neck Surg 2020 09;146(9):801-809

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.

Importance: Tinnitus has a prevalence of 10% to 25% and is frequently associated with numerous complications, such as neuropsychiatric disease. Traditional treatments have failed to meet the needs of patients with tinnitus. Noninvasive brain stimulation (NIBS) can focally modify cortical functioning and has been proposed as a strategy for reducing tinnitus severity. However, the results have been inconclusive.

Objective: To evaluate the association between different central NIBS therapies and efficacy and acceptability for treatment of tinnitus.

Data Sources: ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, and Web of Science databases were searched from inception to August 4, 2019. No language restriction was applied. Manual searches were performed for potentially eligible articles selected from the reference lists of review articles and pairwise meta-analyses.

Study Selection: Randomized clinical trials (RCTs) examining the central NIBS method used in patients with unilateral or bilateral tinnitus were included in the current network meta-analysis. The central NIBS method was compared with sham, waiting list, or active controls. Studies that were not clinical trials or RCTs and did not report the outcome of interest were excluded.

Data Extraction And Synthesis: Two authors independently screened the studies, extracted the relevant information, and evaluated the risk of bias in the included studies. In cases of discrepancy, a third author became involved. If manuscript data were not available, the corresponding authors or coauthors were approached to obtain the original data. This network meta-analysis was based on the frequentist model.

Main Outcomes And Measures: The primary outcome was change in the severity of tinnitus. Secondary outcomes were changes in quality of life and the response rate related to the NIBS method in patients with tinnitus.

Results: Overall, 32 unique RCTs were included with 1458 unique participants (mean female proportion, 34.4% [range, 0%-81.2%]; mean age, 49.6 [range, 40.0-62.8] years; median age, 49.8 [interquartile range, 48.1-52.4] years). The results of the network meta-analysis revealed that cathodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex combined with transcranial random noise stimulation over the bilateral auditory cortex was associated with the greatest improvement in tinnitus severity (standardized mean difference [SMD], -1.89; 95% CI, -3.00 to -0.78) and quality of life (SMD, -1.24; 95% CI, -2.02 to -0.45) compared with the controls. Improvement in tinnitus severity ranked more favorably for continuous theta-burst stimulation (cTBS) over both auditory cortices (SMD, -0.79; 95% CI = -1.57 to -0.01) than cTBS over only the left auditory cortex (SMD, -0.30; 95% CI, -0.87 to 0.28), compared with controls. Repetitive transcranial magnetic stimulation with priming had a superior beneficial association with tinnitus severity compared with the strategies without priming. None of the investigated NIBS types had a significantly different dropout rate compared with that of the control group.

Conclusions And Relevance: This network meta-analysis suggests a potential role of NIBS interventions in tinnitus management. Future large-scale RCTs focusing on longer follow-up and different priming procedure NIBS are warranted to confirm these findings.
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http://dx.doi.org/10.1001/jamaoto.2020.1497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349076PMC
September 2020
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