Mortality and Lithium-Protective Effects after First-Episode Mania Diagnosis in Bipolar Disorder: A Nationwide Retrospective Cohort Study in Taiwan.

INTRODUCTION: This study aimed to estimate all-cause mortality in patients after a first-episode mania (FEM) and examine whether six guideline-recommended medications can reduce mortality. METHODS: The cohort included population-based FEM samples and matched controls from Taiwan, spanning 2007 to 2018. The primary outcomes assessed were all-cause/suicide-related mortality, while the secondary outcome focused on mortality associated with pharmacological treatments. We compared mortality in post-FEM patients and age-/sex-matched controls without any diagnosed bipolar disorders and patients with and without psychopharmacological treatment using Cox regression analysis, respectively. Statistics were presented with time-to-event adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). RESULTS: The study included 54,092 post-FEM patients and 270,460 controls, totaling 2,467,417 person-years of follow-up. Post-FEM patients had higher risks of all-cause mortality (AHR 2.38, 95% CI: 2.31-2.45) and suicide death (10.80, 5.88-19.84) than controls. Lithium (0.62, 0.55-0.70), divalproex (0.89, 0.83-0.95), and aripiprazole (0.81, 0.66-1.00) were associated with reduced all-cause mortality compared to non-users. There were no significant all-cause mortality differences for quetiapine (0.95, 0.89-1.01), risperidone (0.92, 0.82-1.02), and paliperidone (1.24, 0.88-1.76) users. When accounting for drug action onset times in sensitivity analyses, only lithium significantly reduced all-cause mortality (AHR range 0.65-0.72). There were 35 and 16 suicide deaths in post-FEM patients and controls, respectively. No drug had a significant effect on suicide deaths (lithium: 6; divalproex: 7; aripiprazole: 0; quetiapine: 10; risperidone: 4; paliperidone: 1). CONCLUSION: Post-FEM patients had a higher risk of all-cause/suicide-related mortality, and lithium treatment might reduce all-cause mortality.

Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

INTRODUCTION: Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. METHODS: We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). RESULTS: We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. CONCLUSIONS: This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. TRIAL REGISTRATION: PROSPERO CRD42023391562.

Efficacy and acceptability of different probiotic products plus laxatives for pediatric functional constipation: a network meta-analysis of randomized controlled trials.

The prevalence of pediatric constipation ranges from 0.7 to 29.6% across different countries. Functional constipation accounts for 95% of pediatric constipation, and the efficacy of pharmacotherapy is limited, with a success rate of 60%. Several randomized controlled trials (RCTs) have shown the benefits of probiotic supplements in treating this condition. However, the reported strains of probiotics varied among the RCTs. We aimed to compare the efficacy and acceptability of different probiotic supplements for pediatric functional constipation. The current frequentist model-based network meta-analysis (NMA) included RCTs of probiotic supplements for functional constipation in children. The primary outcome was changes in bowel movement or stool frequency; acceptability outcome was all-cause discontinuation. Nine RCTs were included (N = 710; mean age = 5.5 years; 49.4% girls). Most probiotic products, used either alone or combined with laxatives, were associated with significantly better improvement in bowel movement or stool frequency than placebo/control. Protexin plus laxatives (standardized mean difference (SMD) = 1.87, 95% confidence interval (95% CI) = 0.85 to 2.90) were associated with the greatest improvement in bowel movement or stool frequency among all the investigated probiotic products. For the single probiotic interventions, only Lactobacillus casei rhamnosus Lcr35 was associated with significant efficacy compared to placebo/control treatments (SMD = 1.37, 95% CI: 0.32 to 2.43). All the investigated probiotic products had fecal incontinence and patient drop-out rates similar to those of placebo/control treatments.  Conclusion: The results of our NMA support the application of an advanced combination of probiotics and laxatives for pediatric functional constipation if there is no concurrent contraindication.  Registration: PROSPERO (CRD42022298724). What is Known: • Despite of the high prevalence of pediatric constipation, which ranges from 0.7% to 29.6%, the efficacy of pharmacotherapy is limited, with a success rate of 60%. Several randomized controlled trials (RCTs) have shown the benefits of probiotic supplements in treating this condition. However, the reported strains of probiotics varied among the RCTs. The widely heterogeneous strains of probiotics let the traditional meta-analysis, which pooled all different strains into one group, be nonsense and insignificant. What is New: • By conducting a comprehensive network meta-analysis, we aimed to compare the efficacy and acceptability of different strains of probiotic supplements for pediatric functional constipation. Network meta-analysis of nine randomized controlled trials revealed that the most probiotic products, used either alone or combined with laxatives, were associated with significantly better improvement in bowel movement or stool frequency than placebo/control. Protexin plus laxatives was associated with the greatest improvement in bowel movement or stool frequency among all the investigated probiotic products. For the single probiotic interventions, only Lactobacillus casei rhamnosus Lcr35 was associated with significant efficacy compared to placebo/control treatments. All the investigated probiotic products had fecal incontinence and patient drop-out rates similar to those of placebo/control treatments.

Prophylaxis for paediatric emergence delirium in desflurane-based anaesthesia: a network meta-analysis.

PURPOSE: The prevalence of postoperative emergence delirium in paediatric patients (pedED) following desflurane anaesthesia is considerably high at 50-80%. Although several pharmacological prophylactic strategies have been introduced to reduce the risk of pedED, conclusive evidence about the superiority of these individual regimens is lacking. The aim of the current study was to assess the potential prophylactic effect and safety of individual pharmacotherapies in the prevention of pedED following desflurane anaesthesia. METHODS: This frequentist model network meta-analysis (NMA) of randomized controlled trials (RCTs) included peer-reviewed RCTs of either placebo-controlled or active-controlled design in paediatric patients under desflurane anaesthesia. RESULTS: Seven studies comprising 573 participants were included. Overall, the ketamine + propofol administration [odds ratio (OR) = 0.05, 95% confidence intervals (95%CIs) 0.01-0.33], dexmedetomidine alone (OR = 0.13, 95%CIs 0.05-0.31), and propofol administration (OR = 0.30, 95%CIs 0.10-0.91) were associated with a significantly lower incidence of pedED than the placebo/control groups. In addition, only gabapentin and dexmedetomidine were associated with a significantly higher improvement in the severity of emergence delirium than the placebo/control groups. Finally, the ketamine + propofol administration was associated with the lowest incidence of pedED, whereas gabapentin was associated with the lowest severity of pedED among all of the pharmacologic interventions studied. CONCLUSIONS: The current NMA showed that ketamine + propofol administration was associated with the lowest incidence of pedED among all of the pharmacologic interventions studied. Future large-scale trials to more fully elucidate the comparative benefits of different combination regimens are warranted. TRIAL REGISTRATION: PROSPERO CRD42021285200.

Effectiveness of Electroencephalography Neurofeedback for Improving Working Memory and Episodic Memory in the Elderly: A Meta-Analysis.

Background and Objective: Existing evidence indicates the potential benefits of electroencephalography neurofeedback (NFB) training for cognitive function. This study aims to comprehensively review all available evidence investigating the effectiveness of NFB on working memory (WM) and episodic memory (EM) in the elderly population. Material and Methods: A systematic search was conducted across five databases to identify clinical trials examining the impact of NFB on memory function in healthy elderly individuals or those with mild cognitive impairment (MCI). The co-primary outcomes focused on changes in WM and EM. Data synthesis was performed using a random-effects meta-analysis. Results: Fourteen clinical trials (n = 284) were included in the analysis. The findings revealed that NFB was associated with improved WM (k = 11, reported as Hedges' g = 0.665, 95% confidence [CI] = 0.473 to 0.858, p < 0.001) and EM (k = 12, 0.595, 0.333 to 0.856, p < 0.001) in the elderly, with moderate effect sizes. Subgroup analyses demonstrated that NFB had a positive impact on both WM and EM, not only in the healthy population (WM: k = 7, 0.495, 0.213 to 0.778, p = 0.001; EM: k = 6, 0.729, 0.483 to 0.976, p < 0.001) but also in those with MCI (WM: k = 6, 0.812, 0.549 to 1.074, p < 0.001; EM: k = 6, 0.503, 0.088 to 0.919, p = 0.018). Additionally, sufficient training time (totaling more than 300 min) was associated with a significant improvement in WM (k = 6, 0.743, 0.510 to 0.976, p < 0.001) and EM (k = 7, 0.516, 0.156 to 0.876, p = 0.005); however, such benefits were not observed in groups with inadequate training time. Conclusions: The results suggest that NFB is associated with enhancement of both WM and EM in both healthy and MCI elderly individuals, particularly when adequate training time (exceeding 300 min) is provided. These findings underscore the potential of NFB in dementia prevention or rehabilitation.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), somatic and fatigue symptoms in cardiovascular diseases comorbid major depressive disorder (MDD): A randomized controlled trial.

INTRODUCTION: Cardiovascular diseases (CVDs) and major depressive disorder (MDD) are the two most disabling diseases. Patients with CVDs comorbid depression had somatic and fatigue symptoms and were associated with chronic inflammation and omega-3 polyunsaturated fatty acid (n-3 PUFA) deficits. However, there have been limited studies on the effects of n-3 PUFAs on somatic and fatigue symptoms in patients with CVDs comorbid MDD. METHOD: Forty patients with CVDs comorbid MDD (58% males, mean age of 60 ± 9 years) were enrolled and randomised to receive either n-3 PUFAs (2 g of eicosapentaenoic acid [EPA] and 1 g of docosahexaenoic acid[DHA] per day) or placebo in a 12-week double-blind clinical trial. We assessed the somatic symptoms with Neurotoxicity Rating Scale (NRS) and fatigue symptoms with Fatigue Scale at baseline, weeks 1, 2, 4, 8 and 12, as well as blood levels of Brain-Derived Neurotrophic Factor (BDNF), inflammatory biomarkers and PUFAs, at the baseline and week 12. RESULTS: The n-3 PUFAs group had a greater reduction in Fatigue scores than the placebo group at Week 4 (p =.042), while there were no differences in the changes of NRS scores. N-3 PUFAs group also had a greater increase in EPA (p =.001) and a greater decrease in total n-6 PUFAs (p =.030). Moreover, in the subgroup analyses in the younger age group (age < 55), the n-3 PUFAs group had a greater reduction on NRS total scores at Week 12 (p =.012) and NRS Somatic scores at Week 2 (p =.010), Week 8 (p =.027), Week 12 (p =.012) than the placebo group. In addition, the pre- and post-treatment changes of EPA and total n-3 PUFAs levels were negatively associated with the changes of NRS scores at Weeks 2, 4, and 8 (all p <.05), and the changes of BDNF levels were negatively associated with NRS scores at Weeks 8 and 12 (both p <.05) in the younger age group. In the older age group (age ≥ 55), there were a lesser reduction on NRS scores at Weeks 1, 2 and 4 (all p <.05), but a greater reduction on Fatigue score at Week 4 (p =.026), compared to the placebo group. There was no significant correlation between the changes of blood BDNF, inflammation, PUFAs and NRS and Fatigue scores in general and in the older age group. CONCLUSION: Overall, n-3 PUFAs improved the fatigue symptoms in patients with CVDs comorbid MDD and the general somatic symptoms in specific subpopulation of younger age patients, and perhaps via the interplay between BDNF and EPA. Our findings provide promising rationales for future studies to investigate the treatment effects of omega-3 fatty acids on fatigue and somatic symptoms of chronic mental and medical diseases.

Efficacy and acceptability of anti-inflammatory eicosapentaenoic acid for cognitive function in Alzheimer's dementia: A network meta-analysis of randomized, placebo-controlled trials with omega-3 fatty acids and FDA-approved pharmacotherapy.

Alzheimer's dementia (AD) is a major contributor to global disability, and effective therapies to modify disease progression are currently lacking. The neuro-inflammatory theory is a potential etiology underlying this neurodegenerative disease. Previous randomized, controlled trials (RCTs) have provided inconclusive results regarding efficacy of omega-3 polyunsaturated fatty acids (PUFAs) regimens, which might provide anti-inflammatory benefits in the management of AD, in improving cognitive function among participants with AD. The objective of this frequentist-model based network meta-analysis (NMA) was to evaluate the potential advantages of omega-3 PUFAs and currently FDA-approved medications for AD on overall cognitive function in AD individuals. The primary outcomes were: (1) changes in cognitive function, and (2) acceptability, which refers to all-cause discontinuation. Additionally, secondary outcomes included quality of life, behavioral disturbances and safety/tolerability, which was assessed through the frequency of any reported adverse event. This NMA included 52 RCTs (6 with omega-3 PUFAs and 46 with FDA-approved medications) involving 21,111 participants. The results showed that long-term high-dose (1500-2000 mg/day) of eicosapentaenoic acid (EPA)-dominant omega-3 PUFAs augmented with anti-oxidants had the highest potential for cognitive improvement among all investigated treatments [standardized mean difference = 3.00, 95% confidence intervals (95 %CIs) = 1.84-4.16]. Compared to placebo, omega-3 PUFAs had similar acceptability [odds ratio (OR) = 0.46, 95 %CIs = 0.04 to 5.87] and safety profiles (OR = 1.24, 95 %CIs = 0.66 to 2.33)o. These findings support the potential neurotherapeutic effects of high dosage EPA-dominant omega-3 PUFAs for the amelioration of cognitive decline in patients with AD. Future large-scale, long-term RCTs should focus on different dosages of EPA-dominant omega-3 PUFAs regimens on improving cognitive dysfunction in patients with AD at different levels of inflammatory status and psychopathology.

Treatment Efficacy of Pharmacotherapies for Frontotemporal Dementia: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The neuropsychiatric symptoms of frontotemporal dementia (FTD) have a profound negative impact on disease outcomes and care burden. Available pharmacotherapies might be supported by small-scale randomized controlled trials (RCTs); however, clinical recommendations might not be conclusive. METHODS: We systematically searched several databases from inception to April 30, 2022, for RCTs of drug therapy in patients with FTD and neuropsychiatric symptoms (primary outcome). Secondary outcomes included changes in caregiver stress, daily interactive activities, cognitive function, and acceptability (adverse event or dropout rates). The network meta-analysis (NMA) procedure was performed under the frequency model, showing effect sizes as standardized mean differences (SMD) or odds ratios (OR) with 95% confidence intervals (95% CIs). RESULTS: Seven RCTs with 243 participants were included. Compared with placebo, high-dose oxytocin (72 international units) was associated with the greatest improvement in patients' neuropsychiatric symptoms (SMD = -1.17, 95% CIs = -2.25 to -0.08, z = -2.10, p = 0.035). Piracetam significantly worsened neuropsychiatric symptoms (SMD = 3.48, 95% CIs = 1.58 to 5.37, z = 3.60, p < 0.001) and caregiver stress (SMD = 2.40, 95% CIs = 0.80-4.01, z = 2.94, p = 0.003). Trazodone had significantly higher rates of adverse events (OR = 9.53, 95% CIs = 1.85-49.20, z = 2.69, p = 0.007). No pharmacological intervention significantly benefited cognitive function. CONCLUSIONS: This study provides the first NMA for clinical recommendation to support the use of high-dose oxytocin and caution regarding the use of piracetam for neuropsychiatric symptoms in patients with FTD.

Ramelteon for delirium prevention in hospitalized patients: An updated meta-analysis and trial sequential analysis of randomized controlled trials.

Although ramelteon has been examined as a relatively new therapeutic option for delirium prevention, current evidence to evaluate its efficacy is limited. We conducted an updated meta-analysis and examine the reliability of existing evidence regarding the effect of ramelteon on delirium prevention in hospitalized patients. Seven major electronic databases were systematically searched to identify randomized controlled trials examining the efficacy of ramelteon in delirium prevention. Data were pooled using a frequentist-restricted maximum-likelihood random-effects model. A trial sequential analysis was performed using relative risk reduction thresholds of 50%. The primary outcome was the incidence of delirium (reported as odds ratio with 95% confidence intervals). The secondary outcomes were the days of delirium, all-cause mortality, and all-cause discontinuation. Of 187 potentially eligible studies identified, 8 placebo-controlled randomized controlled trials (n = 587) were included. This updated meta-analysis showed that ramelteon was associated with lower odds of delirium occurrence than placebo (0.50; 0.29-0.86; I2 = 17.48%). In trial sequential analysis, the effect of ramelteon across the superiority boundary when using a relative risk reduction threshold ranging from 40% to 60%. In subgroup analyses, ramelteon compared with placebo was associated with lower odds of delirium occurrence in the elderly group (k = 5; 0.28; 0.09-0.85; I2 = 27.93%) and multiple dosage group (k = 5; 0.34; 0.14-0.82; I2 = 44.24%) but not in the non-elderly and non-multiple dosage groups. When considering surgical patients and medical patients separately, ramelteon showed a trend in the treatment of delirium prevention in both groups, while these findings were not statistically significant. No significant between-group differences were found in the secondary outcomes. The current meta-analysis provides updated and reliable evidence that ramelteon, in comparison with placebo, reduces the risk of delirium among hospitalized patients.

Comparisons of Quality, Correctness, and Similarity Between ChatGPT-Generated and Human-Written Abstracts for Basic Research: Cross-Sectional Study.

BACKGROUND: ChatGPT may act as a research assistant to help organize the direction of thinking and summarize research findings. However, few studies have examined the quality, similarity (abstracts being similar to the original one), and accuracy of the abstracts generated by ChatGPT when researchers provide full-text basic research papers. OBJECTIVE: We aimed to assess the applicability of an artificial intelligence (AI) model in generating abstracts for basic preclinical research. METHODS: We selected 30 basic research papers from Nature, Genome Biology, and Biological Psychiatry. Excluding abstracts, we inputted the full text into ChatPDF, an application of a language model based on ChatGPT, and we prompted it to generate abstracts with the same style as used in the original papers. A total of 8 experts were invited to evaluate the quality of these abstracts (based on a Likert scale of 0-10) and identify which abstracts were generated by ChatPDF, using a blind approach. These abstracts were also evaluated for their similarity to the original abstracts and the accuracy of the AI content. RESULTS: The quality of ChatGPT-generated abstracts was lower than that of the actual abstracts (10-point Likert scale: mean 4.72, SD 2.09 vs mean 8.09, SD 1.03; P<.001). The difference in quality was significant in the unstructured format (mean difference -4.33; 95% CI -4.79 to -3.86; P<.001) but minimal in the 4-subheading structured format (mean difference -2.33; 95% CI -2.79 to -1.86). Among the 30 ChatGPT-generated abstracts, 3 showed wrong conclusions, and 10 were identified as AI content. The mean percentage of similarity between the original and the generated abstracts was not high (2.10%-4.40%). The blinded reviewers achieved a 93% (224/240) accuracy rate in guessing which abstracts were written using ChatGPT. CONCLUSIONS: Using ChatGPT to generate a scientific abstract may not lead to issues of similarity when using real full texts written by humans. However, the quality of the ChatGPT-generated abstracts was suboptimal, and their accuracy was not 100%.

Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis.

AIM: Many randomized controlled trials (RCTs) have investigated the use of interleukin 6 antagonists for the treatment of coronavirus disease 2019 (COVID-19), yielding inconsistent results. This network meta-analysis (NMA) aimed to identify the source of these inconsistent results by reassessing whether participants treated with standard of care (SoC) plus placebo have different all-cause mortality from those treated with SoC alone and to reevaluate the efficacy of interleukin 6 antagonists in the treatment of COVID-19. METHODS: We conducted a systematic search for relevant RCTs from the inception of electronic databases through 1 September 2022. The primary outcome was all-cause mortality. The secondary outcomes were the incidences of major medical events, secondary infections, all-cause discontinuation, and serious adverse events. RESULTS: The results of NMA of 33 RCTs showed that patients with COVID-19 treated with SoC plus placebo had lower odds of all-cause mortality than those who received SoC alone (OR, 0.75 [95% confidence interval, 0.58-0.97]). This finding remained consistent after excluding studies with no incident deaths. In addition, when we consider the impact of the widely promoted COVID-19 vaccination and newly developed antiviral treatment strategy, the results from the analysis of the RCT published in 2021 and 2022 remained similar. CONCLUSION: These findings suggest the potential influence of placebo effects on the treatment outcomes of COVID-19 in RCTs. When evaluating the efficacy of treatment strategies for COVID-19, it is crucial to consider the use of placebo in the design of clinical trials.

The efficacy of exogenous melatonin supplement in ameliorating irritable bowel syndrome severity: A meta-analysis of randomized controlled trials.

BACKGROUND: Irritable bowel syndrome (IBS) was found in 11% of the general population worldwide. The current pharmacologic management of IBS was unsatisfactory, and it was accompanied by a number of adverse events. Melatonin was found to play an important role in gastrointestinal smooth muscle motility. Dysregulation of endogenous melatonin secretion has been found in IBS patients. Exogenous melatonin supplement has become one alternative treatment for IBS, but the evidence is inconclusive. The current meta-analysis sought to determine the efficacy of exogenous melatonin supplement in improving IBS severity in IBS patients. METHODS: We included randomized controlled trials (RCTs) that investigated the efficacy of exogenous melatonin supplement in ameliorating IBS severity in IBS patients. This meta-analysis was conducted using a random effects model. The primary target outcomes were changes in IBS severity associated with melatonin or placebo. RESULTS: This meta-analysis of 4 RCTs and 115 participants revealed that exogenous melatonin supplement was associated with significantly better improvement in overall IBS severity than placebo (k = 4, Hedges' g = 0.746, 95% confidence intervals = 0.401-1.091, p < 0.001). The subgroup without concurrent medication had the same result (p < 0.001). In addition, exogenous melatonin supplement was also associated with significantly better improvement in IBS pain severity (p < 0.001) and quality of life (p = 0.007) than placebo, but not in abdominal distension (p = 0.111) or sleep quality (p = 0.142). Finally, melatonin was associated with similar safety profiles with placebo. CONCLUSION: This meta-analysis provides evidence for the use of exogenous melatonin in IBS patients to ameliorate overall IBS severity, IBS pain severity, and quality of life. TRIAL REGISTRATION: PROSPERO CRD42021269451.

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

Multiple comparison of different noninvasive brain stimulation and pharmacologic interventions in patients with methamphetamine use disorders: A network meta-analysis of randomized controlled trials.

AIM: In recent decades, the prevalence of amphetamine and methamphetamine use disorders has at least doubled in some regions/countries, with accompanying high risks of drug overdose-associated mortality. Noninvasive brain stimulation (NIBS) methods may be effective treatments. However, the comparative efficacy of the NIBS protocol for amphetamine/methamphetamine use disorder (AUD/MUD) remains unknown to date. The aim of this network meta-analysis (NMA) was to compare the efficacy and acceptability of various NIBS methods/protocols for AUD/MUD management. METHODS: A frequentist model-based NMA was conducted. We included randomized controlled trials (RCTs) that investigated the efficacy of NIBS and guideline-recommended pharmacologic treatments to reduce craving severity in patients with either AUD or MUD. RESULTS: Twenty-two RCTs including 1888 participants met the eligibility criteria. Compared with the sham/placebo group (study = 19, subjects = 891), a combination of intermittent theta burst stimulation over the left dorsolateral prefrontal cortex (DLPFC) and continuous TBS over the left ventromedial prefrontal cortex (study = 1, subjects = 19) was associated with the largest decreases in craving severity [standardized mean difference (SMD) = -1.50; 95% confidence intervals (95%CIs) = -2.70 to -0.31]. High-frequency repetitive transcranial magnetic stimulation over the left DLPFC was associated with the largest improvements in depression and quality of sleep (study = 3, subjects = 86) (SMD = -2.48; 95%CIs = -3.25 to -1.71 and SMD = -2.43; 95%CIs = -3.38 to -1.48, respectively). The drop-out rate of most investigated treatments did not significantly differ between groups. CONCLUSION: The combined TBS protocol over the prefrontal cortex was associated with the greatest improvement in craving severity. Since few studies were available for inclusion, additional large-scale randomized controlled trials are warranted.

The association of changes of sleep architecture related to donepezil: A systematic review and meta-analysis.

BACKGROUND: Donepezil had been recognized to have impact on sleep quality in demented patients. However, there was insufficient evidences about the actual effect of donepezil in the sleep architectures. Our meta-analysis aimed to evaluate the changes of sleep architectures related to donepezil use. METHODS: Followed the PRISMA2020 and AMSTAR2 guidelines, electronic search had been performed on the databases of PubMed, Embase, ScienceDirect, ClinicalKey, Cochrane CENTRAL, ProQuest, Web of Science, and ClinicalTrials.gov. The outcome measurement was changes of sleep parameters detected by polysomnography. A random-effects meta-analysis was conducted. RESULTS: Total twelve studies had been involved. The percentage of REM sleep would significantly increase after donepezil treatment (Hedges' g = 0.694, p < 0.001). Compared to placebo/controls, subjects with donepezil would had significantly increased percentage of REM sleep stage (Hedges' g = 0.556, p = 0.018). Furthermore, donepezil was also associated with the decreased stage 2 sleep percentage, sleep efficiency, or total sleep time in different analysis conditions. CONCLUSION: Our meta-analysis provided detailed changes of sleep architectures related to donepezil treatment. Further larger sample size studies with stricter control of potential moderators are needed to clarify these issues.

Effectiveness and acceptability of noninvasive brain and nerve stimulation techniques for migraine prophylaxis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Current pharmacologic prophylactic strategies for migraine have exhibited limited efficacy, with response rates as low as 40%-50%. In addition to the limited efficacy, the acceptability of those pharmacologic prophylactic strategies were unacceptable. Although noninvasive brain/nerve stimulation strategies may be effective, the evidence has been inconsistent. The aim of this network meta-analysis (NMA) was to compare strategies of noninvasive brain/nerve stimulation for migraine prophylaxis with respect to their effectiveness and acceptability. METHODS: The PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov , ClinicalKey, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of June 4th, 2021 for randomized controlled trials (RCTs). Patients with diagnosis of migraine, either episodic migraine or chronic migraine, were included. All NMA procedures were conducted under the frequentist model. RESULTS: Nineteen RCTs were included (N = 1493; mean age = 38.2 years; 82.0% women). We determined that the high frequency repetitive transcranial magnetic stimulation (rTMS) over C3 yielded the most decreased monthly migraine days among all the interventions [mean difference = - 8.70 days, 95% confidence intervals (95%CIs): - 14.45 to - 2.95 compared to sham/control groups]. Only alternating frequency (2/100 Hz) transcutaneous occipital nerve stimulation (tONS) over the Oz (RR = 0.36, 95%CIs: 0.16 to 0.82) yielded a significantly lower drop-out rate than the sham/control groups did. CONCLUSIONS: The current study provided a new direction for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on migraine prophylaxis in participants with migraine by different noninvasive brain/nerve stimulation, especially the application of rTMS and tONS. TRIAL REGISTRATION: CRD42021252638. The current study had been approval by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).

Tinnitus Associated with Mild Osteomyelitis of the Temporal Bone Reversed after Conservative Antibiotic Treatment: A Case Series.

The symptomatology and diagnostic tools for osteomyelitis of the temporal bone have not been well documented. Diagnosis of early stage (i.e., mild form) osteomyelitis of the temporal bone may be delayed due to the limitations of traditional computed tomography's (CT) imaging resolution. With the advancement of high-resolution CT (HRCT) images, clinicians can now observe images that could not be observed with traditional CT imaging. In this neuro-image report, we present three patients with refractory/untreatable tinnitus. In their HRCT images, mild osteomyelitis of the temporal bone was revealed by mucosa thickening with bony sequestration of air cells, mild opacification of the air cells, and soft tissue density in the middle ear cavity, mild opacification, and bony sequestration attributed to mucosa thickening of the mastoid air cells (along with the cortical bone). All of the clinical presentations and findings in the pure tone audiometry of the reported patients improved after adequate antibiotic treatment. The current report highlights the potential benefit of HRCT to diagnose this in such patients. In addition, immediate and conservative antibiotic treatment is recommended for managing these patients shortly after the detection of mild osteomyelitis of the temporal bone. This treatment could reduce the risk of progression to the severe form.

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

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.

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

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.