Effect of cranial electrotherapy stimulation as an add-on therapy on late-life generalized anxiety disorder: An open-label study.

INTRODUCTION: Cranial electrotherapy stimulation (CES) is beneficial in reducing anxiety in psychiatric patients. However, no studies have reported on elderly patients with generalized anxiety disorders (GAD). This study aimed to determine the efficacy and safety of a 6-week CES intervention for late-life GAD. MATERIALS AND METHODS: This single-arm pilot study assessed 6-week CES treatment (Alpha-Stim AID) for late-life GAD and 4-week follow-up post intervention. The Hamilton Rating Scale for Anxiety (HAMA) and Beck Anxiety Inventory (BAI) were used as baseline and outcome measures at weeks 4, 6, and 10, respectively. Treatment response was defined as 50 % or more reduction of the HAMA score and remission was defined as a of score ≤7 on the HAMA. Other measures included depression, sleep quality, and quality of life assessment. RESULTS: We included participants (n = 27) aged 68.0 ± 5.0 years, 81.5 % of whom were female. Fifteen (55.6 %), 18 (66.7 %), and 15 (55.6 %) patients were concurrently treated with antidepressants, BZDs, and antipsychotics, respectively. Intention-to-treat (ITT) analysis revealed a significant decrease in HAMA scores from baseline (20.96 ± 3.30) to week 6 (12.26 ± 7.09) and one-month (12.85 ± 7.08) follow-up at W10 (all p < 0.001). The response and remission rates were 33.3 %, 40.7 %, and 48.1 % and 25.9 %, 29.6 %, and 25.9 % at W4, W6, and W10, respectively. The CES improved depression and sleep conditions as measured by the Beck Depression Inventory-II and Pittsburgh Sleep Quality Index. CONCLUSIONS: CES clinically reduces symptoms of anxiety and depression and may improve sleep quality in late-life GAD. Future randomized controlled study is needed.

Comparing the performance of ChatGPT GPT-4, Bard, and Llama-2 in the Taiwan Psychiatric Licensing Examination and in differential diagnosis with multi-center psychiatrists.

AIM: Large language models (LLMs) have been suggested to play a role in medical education and medical practice. However, the potential of their application in the psychiatric domain has not been well-studied. METHOD: In the first step, we compared the performance of ChatGPT GPT-4, Bard, and Llama-2 in the 2022 Taiwan Psychiatric Licensing Examination conducted in traditional Mandarin. In the second step, we compared the scores of these three LLMs with those of 24 experienced psychiatrists in 10 advanced clinical scenario questions designed for psychiatric differential diagnosis. RESULT: Only GPT-4 passed the 2022 Taiwan Psychiatric Licensing Examination (scoring 69 and ≥ 60 being considered a passing grade), while Bard scored 36 and Llama-2 scored 25. GPT-4 outperformed Bard and Llama-2, especially in the areas of 'Pathophysiology & Epidemiology' (χ2 = 22.4, P < 0.001) and 'Psychopharmacology & Other therapies' (χ2 = 15.8, P < 0.001). In the differential diagnosis, the mean score of the 24 experienced psychiatrists (mean 6.1, standard deviation 1.9) was higher than that of GPT-4 (5), Bard (3), and Llama-2 (1). CONCLUSION: Compared to Bard and Llama-2, GPT-4 demonstrated superior abilities in identifying psychiatric symptoms and making clinical judgments. Besides, GPT-4's ability for differential diagnosis closely approached that of the experienced psychiatrists. GPT-4 revealed a promising potential as a valuable tool in psychiatric practice among the three LLMs.

The association of total pulses with the efficacy of repetitive transcranial magnetic stimulation for treatment-resistant major depression: A dose-response meta-analysis.

AIM: This study aimed to examine dose-effects of total pulses on improvement of depressive symptoms in patients with treatment-resistant depression (TRD) receiving repetitive transcranial magnetic stimulation (rTMS) over the left dorsal lateral prefrontal cortex (DLPFC). MATERIALS AND METHODS: The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PsycINFO, and ClinicalTrial.gov databases were systematically searched. We included randomized, double-blind, placebo-controlled trials (RCT) that used rTMS over left DLPFC in patients with TRD. Excluded studies were non-TRD, non-RCTs, or combined other brain stimulation interventions. The outcome of interest was the difference between rTMS arms and sham controls in improvement of depressive symptoms in a dose-response manner. A random-effects meta-analysis and dose-response meta-analysis(DRMA) was used to examine antidepressant efficacy of rTMS and association with total pulses. RESULTS: We found that rTMS over left DLPFC is superior to sham controls (reported as standardized mean difference[SMD] with 95% confidence interval: 0.77; 0.56-0.98). The best-fitting model of DRMA was bell-shaped (estimated using restricted cubic spline model; R2 =0.42), indicating that higher doses (>26,660 total pulses) were not associated with increased improvement of depressive symptoms. Stimulation frequency(R2 =0.53) and age(R2 =0.51) were significant moderators for the dose-response curve. Furthermore, 15-20 Hz rTMS was superior to 10 Hz rTMS (0.61, 0.15-1.10) when combining all doses. CONCLUSIONS: Our findings suggest higher doses(total pulses) of rTMS were not always associated with increased improvement of depressive symptoms in patients with TRD, and that the dose-response relationship was moderated by stimulation frequency and age. These associations emphasize the importance of determining dosing parameters to achieve maximum efficacy.

Comparing different non-invasive brain stimulation interventions for bipolar depression treatment: A network meta-analysis of randomized controlled trials.

Non-invasive brain stimulation (NIBS) is a promising treatment for bipolar depression. We systematically searched for randomized controlled trials on NIBS for treating bipolar depression (INPLASY No: 202340019). Eighteen articles (N = 617) were eligible for network meta-analysis. Effect sizes were reported as standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs). Anodal transcranial direct current stimulation over F3 plus cathodal transcranial direct current stimulation over F4 (a-tDCS-F3 +c-tDCS-F4; SMD = -1.18, 95%CIs = -1.66 to -0.69, N = 77), high-definition tDCS over F3 (HD-tDCS-F3; -1.17, -2.00 to -0.35, 25), high frequency deep transcranial magnetic stimulation (HF-dTMS; -0.81, -1.62 to -0.001, 25), and high frequency repetitive TMS over F3 plus low frequency repetitive TMS over F4 (HF-rTMS-F3 +LF-rTMS-F4; -0.77, -1.43 to -0.11, 38) significantly improved depressive symptoms compared to sham controls. Only a-tDCS-F3 +c-tDCS-F4 (OR = 4.53, 95%CIs = 1.51-13.65) and HF-rTMS-F3 +LF-rTMS-F4 (4.69, 1.02-21.56) showed higher response rates. No active NIBS interventions exhibited significant differences in dropout or side effect rates, compared with sham controls.

Electroconvulsive therapy for obsessive compulsive symptoms in a patient with schizophrenia: a brief report.

Comorbid obsessive-compulsive disorder (OCD) is common among patients with schizophrenia. The role of electroconvulsive therapy (ECT) in the treatment of OCD in schizophrenia is unclear. Herein, we present a 45-year-old man who was diagnosed with schizophrenia along with OCD and received ECT due to relapse of psychosis owing to refractive schizophrenia. Together with psychotic symptoms, obvious symptoms of OCD were observed prior to treatment, including obsessive thoughts, difficulty in starting activities, and repetitive and ritualistic behavior. After 12 sessions of ECT, symptoms of schizophrenia and OCD both improved significantly (Positive and Negative Syndrome Scale [PANSS] score decreased from 95 points to 58 points, and Yale - Brown Obsessive-Compulsive Scale [Y-BOCS] score decreased from 29 points to 11 points). Mild aggravation of OCD symptoms was noted 3 months after ECT treatment (Y-BOCS score increased from 11 points to 17 points) without obvious relapse of psychotic symptoms (PANSS score changed from 58 points to 62 points). In conclusion, ECT could be considered as an alternative therapy for patients with schizophrenia and OCD with limited response to pharmacological treatment.

Multimorbidity Pattern and Risk for Mortality Among Patients With Dementia: A Nationwide Cohort Study Using Latent Class Analysis.

OBJECTIVE: Individuals with dementia are at a substantially elevated risk for mortality; however, few studies have examined multimorbidity patterns and determined the inter-relationship between these comorbidities in predicting mortality risk. METHODS: This is a prospective cohort study. Data from 6,556 patients who were diagnosed with dementia between 1997 and 2012 using the Taiwan National Health Insurance Research Database were analyzed. Latent class analysis was performed using 16 common chronic conditions to identify mortality risk among potentially different latent classes. Logistic regression was performed to determine the adjusted association of the determined latent classes with the 5-year mortality rate. RESULTS: With adjustment for age, a three-class model was identified, with 42.7% of participants classified as "low comorbidity class (cluster 1)", 44.2% as "cardiometabolic multimorbidity class (cluster 2)", and 13.1% as "FRINGED class (cluster 3, characterized by FRacture, Infection, NasoGastric feeding, and bleEDing over upper gastrointestinal tract)." The incidence of 5-year mortality was 17.6% in cluster 1, 26.7% in cluster 2, and 59.6% in cluster 3. Compared with cluster 1, the odds ratio for mortality was 9.828 (95% confidence interval [CI]=6.708-14.401; p<0.001) in cluster 2 and 1.582 (95% CI=1.281-1.953; p<0.001) in cluster 3. CONCLUSION: Among patients with dementia, the risk for 5-year mortality was highest in the subpopulation characterized by fracture, urinary and pulmonary infection, upper gastrointestinal bleeding, and nasogastric intubation, rather than cancer or cardiometabolic comorbidities. These findings may improve decision-making and advance care planning for patients with dementia.

Black cohosh extracts in women with menopausal symptoms: an updated pairwise meta-analysis.

OBJECTIVE: Menopausal symptoms are common in midlife women and have broad impacts on their daily functioning and quality of life. Black cohosh extracts have been widely used to relieve menopausal symptoms. However, the comparative benefits of different combined black cohosh regimens remain inconclusive. The aim of the current updated meta-analysis is to address the comparative efficacies of different black cohosh regimens in improving menopausal symptoms. METHODS: Random-effect model pairwise meta-analysis of randomized controlled trials was conducted to investigate the treatment effect on menopausal symptoms by the black cohosh extract both alone or combined with other related active ingredients. The outcomes studied were changes in menopausal symptoms after treatment with black cohosh extracts in menopausal women. RESULTS: Twenty-two articles including information on 2,310 menopausal women were included in the analyses. Black cohosh extracts were associated with significant improvements in overall menopausal symptoms (Hedges' g = 0.575, 95% CI = 0.283 to 0.867, P < 0.001), as well as in hot flashes (Hedges' g = 0.315, 95% CIs = 0.107 to 0.524, P = 0.003), and somatic symptoms (Hedges' g = 0.418, 95% CI = 0.165 to 0.670, P = 0.001), compared with placebo. However, black cohosh did not significantly improve anxiety (Hedges' g = 0.194, 95% CI = -0.296 to 0.684, P = 0.438) or depressive symptoms (Hedges' g = 0.406, 95% CI = -0.121 to 0.932, P = 0.131). The dropout rate for black cohosh products was similar to that for placebo (odds ratio = 0.911, 95% CI = 0.660 to 1.256, P = 0.568). CONCLUSIONS: This study provides updated evidence regarding the potentially beneficial effects of black cohosh extracts for relieving menopausal symptoms in menopausal women.

Risk of suicide after a diagnosis of sleep apnea: A nationwide longitudinal study.

Previous studies have presented evidence on the association between sleep apnea and suicidal ideation and planning, but the relationship between a clinical diagnosis of sleep apnea and suicide attempts remains unknown. We investigated the risk of suicide after a diagnosis with sleep apnea using data from a nationwide community-based population database, i.e., the Taiwan National Health Insurance Research Database. We recruited 7,095 adults with sleep apnea and 28,380 age-, sex-, and comorbidity-matched controls between 1998 and 2010 and followed them up until the end of 2011. Individuals who exhibited any (once or repeated) suicide attempts were identified during the follow-up period. The E value was calculated for unmeasured bias. Sensitivity analysis was conducted. Patients with sleep apnea were more likely to carry out any suicide attempt (hazard ratio: 4.53; 95% confidence interval: 3.48-5.88) during the follow-up period than the controls after adjusting for demographic data, mental disorders, and physical comorbidities. The hazard ratio remained significant after excluding individuals with mental disorders (4.23; 3.03-5.92). The hazard ratio was 4.82 (3.55-6.56) for male patients and 3.86 (2.33-6.38) for female patients. Consistent findings of increased risk of repeated suicide attempt were found among patients with sleep apnea. No association was found between continuous positive airway pressure treatment and suicide risk. The calculated E values support suicide risk after the diagnosis of sleep apnea. The risk of suicide was 4.53-fold higher in patients diagnosed with sleep apnea than in their counterparts without sleep apnea.

Antidepressant drugs use and epilepsy risk: A nationwide nested case-control study.

BACKGROUND: To investigate the association between exposure to antidepressants (ADs) and the risk of epilepsy among patients exposed to ADs. METHOD: We conducted a case-control study using Taiwan's National Health Insurance Research Database between 1998 and 2013. A total of 863 patients with epilepsy and 3,452 controls were included. The dose of ADs was categorized according to the cumulative defined daily dose (cDDD). The risk of epilepsy was assessed using conditional logistic regression analysis. RESULTS: Compared with cDDD < 90, ADs exposure with cDDD > 365 (odds ratio [OR]: 1.37, 95% confidence interval [CI]:1.12-1.68) was associated with an increased risk of epilepsy, but not for those with cDDD 90-365 (OR: 1.07,95% CI: 0.87-1.30) after adjustment for several comorbidities and indications of ADs use. Other identified risk factors include cerebrovascular disease, traumatic brain injury, and central nervous system infection. Subgroup analysis of individual ADs showed that escitalopram (OR: 1.93, 95% CI: 1.12-3.31), venlafaxine (OR: 1.62, 95% CI: 1.13-2.31), mirtazapine (OR: 1.56, 95% CI: 1.00-2.43), paroxetine (OR: 1.44, 95% CI: 1.08-1.94), and fluoxetine (OR: 1.25, 95% CI: 1.01-1.56) had a significantly higher risk of epilepsy. Sertraline, fluvoxamine, citalopram, duloxetine, milnacipran, and bupropion did not show any proconvulsant effects. CONCLUSIONS: The study found an increased risk of epilepsy among patients who were exposed to any ADs, particularly longer-term users. Given the nature of observational studies with residual bias, interpretation should be cautious.

Automated Video Analysis of Audio-Visual Approaches to Predict and Detect Mild Cognitive Impairment and Dementia in Older Adults.

BACKGROUND: Early identification of different stages of cognitive impairment is important to provide available intervention and timely care for the elderly. OBJECTIVE: This study aimed to examine the ability of the artificial intelligence (AI) technology to distinguish participants with mild cognitive impairment (MCI) from those with mild to moderate dementia based on automated video analysis. METHODS: A total of 95 participants were recruited (MCI, 41; mild to moderate dementia, 54). The videos were captured during the Short Portable Mental Status Questionnaire process; the visual and aural features were extracted using these videos. Deep learning models were subsequently constructed for the binary differentiation of MCI and mild to moderate dementia. Correlation analysis of the predicted Mini-Mental State Examination, Cognitive Abilities Screening Instrument scores, and ground truth was also performed. RESULTS: Deep learning models combining both the visual and aural features discriminated MCI from mild to moderate dementia with an area under the curve (AUC) of 77.0% and accuracy of 76.0%. The AUC and accuracy increased to 93.0% and 88.0%, respectively, when depression and anxiety were excluded. Significant moderate correlations were observed between the predicted cognitive function and ground truth, and the correlation was strong excluding depression and anxiety. Interestingly, female, but not male, exhibited a correlation. CONCLUSION: The study showed that video-based deep learning models can differentiate participants with MCI from those with mild to moderate dementia and can predict cognitive function. This approach may offer a cost-effective and easily applicable method for early detection of cognitive impairment.

The beneficial effect on cognition of noninvasive brain stimulation intervention in patients with dementia: a network meta-analysis of randomized controlled trials.

BACKGROUND: Dementia [i.e., Alzheimer disease (AD)], the most common neurodegenerative disease, causes profound negative impacts on executive function and quality of life. Available pharmacological treatments often fail to achieve satisfactory outcomes. Noninvasive brain stimulation (NIBS) techniques, which focally modify cortical function and enhance synaptic long-term potentiation, are potentially beneficial for the cognition in patients with AD. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and safety of different NIBS interventions in patients with AD through NMA. METHODS: Only randomized controlled trials (RCTs) examining NIBS interventions in patients with AD had been included. All NMA procedures were performed under the frequentist model. The primary and secondary outcomes were changes in cognitive function and quality of life, respectively. RESULTS: Nineteen RCTs (639 participants) were included. The mean treatment and follow-up durations were 5.7 and 10.5 weeks, respectively. The combination of cathodal tDCS of the left dorsolateral prefrontal cortex and anodal tDCS over the right supraorbital region (c-tDCS-F3 + a-tDCS-Fp2) was associated with a significant beneficial effect on cognition compared with sham controls (standardized mean difference=2.43, 95% confidence interval=0.61-4.26, n=12 and 11). It was also associated with the greatest beneficial effect on cognition among all the investigated NIBS approaches. All the methods were well tolerated with regard to the safety profile, as reflected in the rates of adverse events or local discomfort, as well as acceptability, as indicated by dropout rate. CONCLUSIONS: The present findings provide evidence of the benefits of NIBS, especially tDCS, for beneficial effect on cognition in patients with AD. However, because of few studies included, this effect was not replicated yet in the other studies. Therefore, future larger-scale and longer follow-up duration RCTs should be warranted. TRIAL REGISTRATION: PROSPERO CRD42020209516. The current study had been approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).

The Clinical Observation of Inflammation Theory for Depression: The Initiative of the Formosa Long COVID Multicenter Study (FOCuS).

There is growing evidence that the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risks of psychiatric sequelae. Depression, anxiety, cognitive impairments, sleep disturbance, and fatigue during and after the acute phase of COVID-19 are prevalent, long-lasting, and exerting negative consequences on well-being and imposing a huge burden on healthcare systems and society. This current review presented timely updates of clinical research findings, particularly focusing on the pathogenetic mechanisms underlying the neuropsychiatric sequelae, and identified potential key targets for developing effective treatment strategies for long COVID. In addition, we introduced the Formosa Long COVID Multicenter Study (FOCuS), which aims to apply the inflammation theory to the pathogenesis and the psychosocial and nutrition treatments of post-COVID depression and anxiety.

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.

Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment.

OBJECTIVE: To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for clozapine-resistant schizophrenia (CRS). METHODS: Six major electronic databases were systematically searched for RCTs published until July 10, 2021. The primary outcome was change in overall symptoms, and the secondary outcomes were positive and negative symptoms and acceptability. We performed random-effects network meta-analysis. Normalized entropy was calculated to examine the uncertainty of treatment ranking. RESULTS: We identified 35 RCTs (1472 patients with 23 active augmentation treatments) with a mean daily clozapine dose of 440.80 (91.27) mg for 1168.22 (710.28) days. Network meta-analysis of overall symptoms (reported as standardized mean difference; 95 % confidence interval) with consistent results indicated that mirtazapine (-4.41; -5.61, -3.21), electroconvulsive therapy (ECT) (-4.32; -5.43, -3.21), and memantine (-2.02; -3.14, -0.91) were ranked as the best three treatments. For positive symptoms, ECT (-5.18; -5.86, -4.49) was ranked the best with less uncertainty. For negative symptoms, memantine (-3.38; -4.50, -2.26), duloxetine (-3.27; -4.25, -2.29), and mirtazapine (-1.73; -2.71, -0.74) were ranked the best three treatments with less uncertainty. All antipsychotics, N-methyl d-aspartate receptor agonists, and antiepileptics were not associated with more efficacy than placebo. Compared to placebo, only amisulpride had statistically significant lower discontinuation rate (risk ratio: 0.21; 95 % CI: 0.05, 0.93). CONCLUSION: Add-on mirtazapine, ECT, and memantine were the most efficacious augmentation options for CRS. Data on other important outcomes such as cognitive functioning or quality of life were rarely reported, making further large-scale, well-designed RCTs necessary. (PROSPERO number, CRD42021262197.).

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

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 (k=5, Hedges' g=-0.414, 95% CI -0.740 to -0.087, p=0.013). The subgroup without psychiatric comorbidities (k=4, Hedges' g=-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.

Risk of Major Mental Disorder after Severe Bacterial Infections in Children and Adolescents: A Nationwide Longitudinal Study.

INTRODUCTION: Evidence has suggested an association between bacterial infection and increased risk of subsequent major mental disorders (MMDs). Whether such association varies with different pathogens remains unclear. We aimed to investigate the risk of subsequent MMDs after exposure to bacterial pathogens in children and adolescents. METHODS: Between 1997 and 2012, we enrolled a nationwide cohort of 14,024 children and adolescents with hospitalized bacterial infection, and noninfected controls were 1:4 matched for demographics. There were 11 investigated pathogens, namely, Streptococcus, Staphylococcus, Pseudomonas, Klebsiella, Hemophilus, Mycoplasma, Tuberculosis, Meningococcus, Escherichia, Chlamydia, and Scrub typhus. The primary outcomes were the subsequent risk of seven MMDs, namely, autism spectrum disorder (ASD), attention-deficiency hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic disorder, schizophrenia, bipolar disorder, and depressive disorder. The secondary outcomes were the subsequent risk of exposure to psychotropic medications. RESULTS: Pooled bacterial infection was associated with increased risk of the six MMDs - ASD (reported as hazard ratios with 95% confidence intervals: 13.80; 7.40-25.75), ADHD (6.93; 5.98-8.03), OCD (3.93; 1.76-8.76), tic disorder (6.19; 4.44-8.64), bipolar disorder (2.50; 1.28-4.86), and depressive disorder (1.93; 1.48-2.51) - and exposure to four psychotropic medications, including ADHD drugs (11.81; 9.72-14.35), antidepressants (2.96; 2.45-3.57), mood stabilizers (4.51; 2.83-7.19), and atypical antipsychotics (4.23; 3.00-5.96) compared to controls. The associations among MMDs and specific pathogens varied. Importantly, Streptococcus was associated with the most MMDs (six MMDs), and ADHD was associated with eight bacterial pathogen infections. CONCLUSIONS: After bacterial infection, the risk of MMDs increased in children and adolescents compared to controls, and such associations varied with different pathogens. Future studies are warranted to validate our study findings and investigate the potential mechanisms.

Diagnostic progression to schizophrenia: A nationwide cohort study of 11 170 adolescents and young adults with autism spectrum disorder.

AIMS: Previous studies have suggested an increased risk of developing schizophrenia later in life in children with autism spectrum disorder (ASD). This study aims to investigate the diagnosis stability and the potential predictors for progression to schizophrenia in ASD. METHODS: We recruited 11 170 adolescents (10-19 years) and young adults (20-29 years) with ASD between 2001 and 2010. They were followed up to the end of 2011 to identify newly diagnosed schizophrenia. The Kaplan-Meier method and Cox regression with age as a time scale were employed to estimate incidence rates and the significance of candidate predictors. RESULTS: The progression rate from ASD to schizophrenia was 10.26% for 10 years of follow-up. Among 860 progressors, 580 (67.44%) occurred within the first 3 years after a diagnosis of ASD. The identified predictors were age (reported as hazard ratio with 95% confidence interval: 1.13; 1.11-1.15), depressive disorder (1.36; 1.09-1.69), alcohol use disorder (3.05; 2.14-4.35), substance use disorder (1.91; 1.18-3.09), cluster A personality disorder (2.95; 1.79-4.84), cluster B personality disorder (1.86; 1.05-3.28), and a family history of schizophrenia (2.12; 1.65-2.74). CONCLUSION: More than two-thirds of the progressors developed schizophrenia within the first 3 years. Demographic characteristics, physical and psychiatric comorbidities, and psychiatric family history were significant predictors of progression.

Dose-Dependent Proton Pump Inhibitor Exposure and Risk of Type 2 Diabetes: A Nationwide Nested Case-Control Study.

Background: To investigate the association between proton pump inhibitor (PPI) exposure and a risk of type 2 diabetes mellitus (T2DM) among patients with upper gastrointestinal disease (UGID). Method: We conducted a case−control study from Taiwan's National Health Insurance Research Database between 1998 and 2013. A total of 20,940 patients with T2DM and 20,940 controls were included. The dose of PPIs was categorized according to the cumulative defined daily dose (cDDD). The risk of T2DM was assessed using conditional logistic regression analysis. Result: Compared with cDDD ≤ 30, higher dosage of PPI exposure was associated with an increased risk of T2DM development: cDDD 31−120 (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.13−1.26); cDDD 121−365 (OR: 1.26, 95% CI: 1.19−1.33); and cDDD > 365 (OR: 1.34, 95% CI: 1.23−1.46). Subgroup analysis of individual PPI showed that pantoprazole (OR: 1.14, 95% CI: 1.07−1.21), lansoprazole (OR: 1.08, 95% CI: 1.03−1.12), and omeprazole (OR: 1.11, 95% CI: 1.06−1.16) have a significantly higher risk of T2DM development. Conclusions: A dose-dependent increased risk of T2DM was found among patients with UGID using higher doses of PPIs compared with those with lower doses of these drugs. Further studies are necessary to investigate the underlying pathophysiology of PPIs and T2DM.

Efficacy and Tolerability of Cranial Electrotherapy Stimulation in the Treatment of Anxiety: A Systemic Review and Meta-Analysis.

Objective: We aimed to investigate the efficacy and tolerability of cranial electrotherapy stimulation (CES) for patients with anxiety symptoms. Method: We searched the Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase and Medline for randomized control trials (RCTs) from the time of inception until November 15, 2021, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were pooled using a random-effects model. The primary outcomes were the mean change scores for anxiety symptoms. The secondary outcomes were the mean change scores for depressive symptoms. Results: Eleven RCTs were eligible (n = 794, mean age: 41.4, mean population of female: 64.8%). CES significantly reduced the anxiety symptoms compared to the control group [k = 11, n = 692, Hedge's g = -0.625, 95% confidence intervals (CIs) = -0.952 to -0.298, P < 0.001] with moderate effect size. The subgroup analysis showed that CES reduced both primary and secondary anxiety (primary anxiety, k =3, n = 288, Hedges' g = -1.218, 95% CIs = -1.418 to -0.968, P = 0.007; secondary anxiety, k = 8, n = 504, Hedges' g = -0.334, 95% CIs = -0.570 to -0.098, P = 0.006). After performing between group analysis, we found CES has significant better efficacy for patients with primary anxiety than those with secondary anxiety (P < 0.001). For secondary outcome, CES significantly reduced depressive symptoms in patients with anxiety disorders (k = 8, n = 552, Hedges' g = -0.648, 95% CIs = -1.062 to -0.234, P = 0.002). No severe side effects were reported and the most commonly reported adverse events were ear discomfort and ear pain. Conclusion: We found CES is effective in reducing anxiety symptoms with moderate effect size in patients with both primary and secondary anxiety. Furthermore, CES was well-tolerated and acceptable.Systematic Review Registration: PROSPERO, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021267916.

Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries.

Autism spectrum disorder (ASD) substantially contributes to the burden of mental disorders. Improved awareness and changes in diagnostic criteria of ASD may have influenced the diagnostic rates of ASD. However, while data on trends in diagnostic rates in some individual countries have been published, updated estimates of diagnostic rate trends and ASD-related disability at the global level are lacking. Here, we used the Global Burden of Diseases, Injuries, and Risk Factors Study data to address this gap, focusing on changes in prevalence, incidence, and disability-adjusted life years (DALYs) of ASD across the world. From 1990 to 2019, overall age-standardized estimates remained stable globally. Both prevalence and DALYs increased in countries with high socio-demographic index (SDI). However, the age-standardized incidence decreased in some low SDI countries, indicating a need to improve awareness. The male/female ratio decreased between 1990 and 2019, possibly accounted for by increasing clinical attention to ASD in females. Our results suggest that ASD detection in low SDI countries is suboptimal, and that ASD prevention/treatment in countries with high SDI should be improved, considering the increasing prevalence of the disorder. Additionally, growing attention is being paid to ASD diagnosis in females, who might have been left behind by ASD epidemiologic and clinical research previously. ASD burden estimates are underestimated as GBD does not account for mortality in ASD.