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Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD = -1.10, 95%CI = -1.75,-0.45), L-lysine (SMD = -1.05,95%CI = -1.55, -0.19), omega-3 fatty acids (SMD = -0.83,95%CI = -1.31, -0.34) and withania somnifera (SMD = -0.71,95%CI = -1.21,-0.22). Citicoline (SMD = -1.05,95%CI = -1.86,-0.23), L-lysine (SMD = -1.04,95%CI = -1.84,-0.24), N-acetylcysteine (SMD = -0.89,95%CI = -1.35,-0.43) and sarcosine (SMD = -0.61,95%CI = -1.02,-0.21) outperformed placebo augmentation of TAU ("any phase"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia are warranted.
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Systematic reviews are a cornerstone for synthesizing the available evidence on a given topic. They simultaneously allow for gaps in the literature to be identified and provide direction for future research. However, due to the ever-increasing volume and complexity of the available literature, traditional methods for conducting systematic reviews are less efficient and more time-consuming. Numerous artificial intelligence (AI) tools are being released with the potential to optimize efficiency in academic writing and assist with various stages of the systematic review process including developing and refining search strategies, screening titles and abstracts for inclusion or exclusion criteria, extracting essential data from studies and summarizing findings. Therefore, in this article we provide an overview of the currently available tools and how they can be incorporated into the systematic review process to improve efficiency and quality of research synthesis. We emphasize that authors must report all AI tools that have been used at each stage to ensure replicability as part of reporting in methods.
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Meta-research, also known as "research on research" is a field of study that investigates the methods, reporting, reproducibility, evaluation, and incentives along the research continuum. Meta-research literacy is imperative to ensure high quality, transparent and reproducible primary data or meta-research products. In this commentary, we propose that early career researchers should be trained in meta-research as a foundation to develop a deeper understanding of the research process and ability to appraise the research literature and design high-quality original studies, irrespective of their chosen field of study. We discuss the importance of meta-research and open science from the perspective of an early career trainee, highlighting essential areas for growth and obstacles one may encounter.
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Importance: Noninvasive brain stimulation (NIBS) interventions have been shown to be efficacious in several mental disorders, but the optimal dose stimulation parameters for each disorder are unknown. Objective: To define NIBS dose stimulation parameters associated with the greatest efficacy in symptom improvement across mental disorders. Data Sources: Studies were drawn from an updated (to April 30, 2023) previous systematic review based on a search of PubMed, OVID, and Web of Knowledge. Study Selection: Randomized clinical trials were selected that tested transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) for any mental disorder in adults aged 18 years or older. Data Extraction and Synthesis: Two authors independently extracted the data. A 1-stage dose-response meta-analysis using a random-effects model was performed. Sensitivity analyses were conducted to test robustness of the findings. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The main outcome was the near-maximal effective doses of total pulses received for TMS and total current dose in coulombs for tDCS. Results: A total of 110 studies with 4820 participants (2659 men [61.4%]; mean [SD] age, 42.3 [8.8] years) were included. The following significant dose-response associations emerged with bell-shaped curves: (1) in schizophrenia, high-frequency (HF) TMS on the left dorsolateral prefrontal cortex (LDLPFC) for negative symptoms (χ2 = 9.35; df = 2; P = .009) and TMS on the left temporoparietal junction for resistant hallucinations (χ2 = 36.52; df = 2; P < .001); (2) in depression, HF-DLPFC TMS (χ2 = 14.49; df = 2; P < .001); (3) in treatment-resistant depression, LDLPFC tDCS (χ2 = 14.56; df = 2; P < .001); and (4) in substance use disorder, LDLPFC tDCS (χ2 = 33.63; df = 2; P < .001). The following significant dose-response associations emerged with plateaued or ascending curves: (1) in depression, low-frequency (LF) TMS on the right DLPFC (RDLPFC) with ascending curve (χ2 = 25.67; df = 2; P = .001); (2) for treatment-resistant depression, LF TMS on the bilateral DLPFC with ascending curve (χ2 = 5.86; df = 2; P = .004); (3) in obsessive-compulsive disorder, LF-RDLPFC TMS with ascending curve (χ2 = 20.65; df = 2; P < .001) and LF TMS on the orbitofrontal cortex with a plateaued curve (χ2 = 15.19; df = 2; P < .001); and (4) in posttraumatic stress disorder, LF-RDLPFC TMS with ascending curve (χ2 = 54.15; df = 2; P < .001). Sensitivity analyses confirmed the main findings. Conclusions and Relevance: The study findings suggest that NIBS yields specific outcomes based on dose parameters across various mental disorders and brain regions. Clinicians should consider these dose parameters when prescribing NIBS. Additional research is needed to prospectively validate the findings in randomized, sham-controlled trials and explore how other parameters contribute to the observed dose-response association.
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Transtornos Mentais , Estimulação Transcraniana por Corrente Contínua , Estimulação Magnética Transcraniana , Humanos , Estimulação Magnética Transcraniana/métodos , Estimulação Transcraniana por Corrente Contínua/métodos , Transtornos Mentais/terapia , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Research on the impact of the COVID-19 pandemic on mothers/childbearing parents has mainly been cross-sectional and focused on psychological symptoms. This study examined the impact on function using ongoing, systematic screening of a representative Ontario sample. METHODS: An interrupted time series analysis of repeated cross-sectional data from a province-wide screening program using the Healthy Babies Healthy Children (HBHC) tool assessed changes associated with the pandemic at the time of postpartum discharge from hospital. Postal codes were used to link to neighborhood-level data. The ability to parent or care for the baby/child and other psychosocial and behavioral outcomes were assessed. RESULTS: The co-primary outcomes of inability to parent or care for the baby/child were infrequently observed in the pre-pandemic (March 9, 2019-March 15, 2020) and initial pandemic periods (March 16, 2020-March 23, 2021) (parent 209/63,006 (0.33%)-177/56,117 (0.32%), care 537/62,955 (0.85%)-324/56,086 (0.58%)). Changes after pandemic onset were not observed for either outcome although a significant (p = 0.02) increase in slope was observed for inability to parent (with questionable clinical significance). For secondary outcomes, worsening was only seen for reported complications during labor/delivery. Significant improvements were observed in the likelihood of being unable to identify a support person to assist with care, need of newcomer support, and concerns about money over time. CONCLUSIONS: There were no substantive changes in concerns about ability to parent or care for children. Adverse impacts of the pandemic may have been mitigated by accommodations for remote work and social safety net policies.
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Individuals with bipolar disorder are at increased risk for suicide, and this can be influenced by a range of biological, clinical, and environmental risk factors. Biological components associated with suicide include DNA modifications that lead to changes in gene expression. Common genetic variation and DNA methylation changes are some of the most frequent types of DNA findings associated with an increased risk for suicidal behavior. Importantly, the interplay between genetic predisposition and DNA methylation patterns is becoming more prevalent in genetic studies. We hypothesized that DNA methylation patterns in specific loci already genetically associated with suicide would be altered in individuals with bipolar disorder and a history of suicide attempt. To test this hypothesis, we searched the literature to identify common genetic variants (N=34) previously associated with suicidal thoughts and behaviors in individuals with bipolar disorder. We then created a customized sequencing panel that covered our chosen genomic loci. We profiled DNA methylation patterns from blood samples collected from bipolar disorder participants with suicidal behavior (N=55) and without suicidal behavior (N=51). We identified seven differentially methylated CpG sites and five differentially methylated regions between the two groups. Additionally, we found that DNA methylation changes in MIF and CACNA1C were associated with lethality or number of suicide attempts. Finally, we identified three meQTLs in SIRT1 , IMPA2 , and INPP1 . This study illustrates that DNA methylation is altered in individuals with bipolar disorder and a history of suicide attempts in regions known to harbor suicide-related variants.
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Delirium is a common condition across different settings and populations. The interventions for preventing and managing this condition are still poorly known. The aim of this umbrella review is to synthesize and grade all preventative and therapeutic interventions for delirium. We searched five databases from database inception up to March 15th, 2023 and we included meta-analyses of randomized controlled trials (RCTs) to decrease the risk of/the severity of delirium. From 1959 records after deduplication, we included 59 systematic reviews with meta-analyses, providing 110 meta-analytic estimates across populations, interventions, outcomes, settings, and age groups (485 unique RCTs, 172,045 participants). In surgery setting, for preventing delirium, high GRADE evidence supported dexmedetomidine (RR=0.53; 95%CI: 0.46-0.67, k=13, N=3988) and comprehensive geriatric assessment (OR=0.46; 95%CI=0.32-0.67, k=3, N=496) in older adults, dexmedetomidine in adults (RR=0.33, 95%CI=0.24-0.45, k=7, N=1974), A2-adrenergic agonists after induction of anesthesia (OR= 0.28, 95%CI= 0.19-0.40, k=10, N=669) in children. High certainty evidence did not support melatonergic agents in older adults for delirium prevention. Moderate certainty supported the effect of dexmedetomidine in adults and children (k=4), various non-pharmacological interventions in adults and older people (k=4), second-generation antipsychotics in adults and mixed age groups (k=3), EEG-guided anesthesia in adults (k=2), mixed pharmacological interventions (k=1), five other specific pharmacological interventions in children (k=1 each). In conclusion, our work indicates that effective treatments to prevent delirium differ across populations, settings, and age groups. Results inform future guidelines to prevent or treat delirium, accounting for safety and costs of interventions. More research is needed in non-surgical settings.
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Delírio , Humanos , Delírio/prevenção & controle , Delírio/terapia , Dexmedetomidina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: There is ongoing uncertainty about whether cannabis use increases the risk of developing an anxiety disorder. In this study we estimated the risk of having an incident healthcare visit for an anxiety disorder following an emergency department (ED) visit for cannabis use and explored factors associated with increased risk. Methods: We used health administrative data to perform a population-based cohort study of all individuals aged 10-105 years with no previous healthcare visits for anxiety disorders in Ontario, Canada, between January 2008 and March 2019. We compared the risk of having an incident healthcare visit for an anxiety disorder in the ED or hospital (primary analysis) or additionally in an outpatient setting (secondary analysis) for individuals with an incident ED visit for cannabis to members of the general population using cumulative incidence functions and cause-specific hazard models adjusted for relevant confounders. Findings: Our study included 12,099,144 individuals aged 10-105 without prior care for an anxiety disorder in the ED or hospital, of which 34,822 (0.29%) had an incident ED visit due to cannabis. Within 3-years of an incident ED visit due to cannabis, 12.3% (n = 4294) of individuals had an incident ED visit or hospitalization for an anxiety disorder-a 3.7-fold (adjusted Hazard Ratio [aHR] 3.69 95% CI 3.57-3.82) increased risk relative to the general population (1.2%). In secondary analysis, further excluding individuals with prior outpatient care for anxiety disorders, 23.6% of individuals with an ED visit due to cannabis had an incident outpatient visit, ED visit, or hospitalization for an anxiety disorder within 3-years compared to 5.6% of individuals in the general population (aHR 3.88 95% CI 3.77-2.99). The risk of having an incident healthcare visit for an anxiety disorder was higher in individuals with ED visits for cannabis use compared to the general population across all age and sex strata. However, younger males with ED visits for cannabis use (aHR 5.67 95% CI 5.19-6.21) had a greater risk relative to the general population than younger women with cannabis use (aHR 3.22 95% CI 2.95-3.52). Interpretation: ED visits for cannabis use were associated with an increased risk of having an incident healthcare visit for an anxiety disorder, particularly in young males. These findings have important clinical and policy implications given the increasing use of cannabis over time and trend towards legalization of cannabis. Funding: Canadian Institutes for Health Research.
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Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.
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Transtorno Bipolar , Adulto , Humanos , Transtorno Bipolar/genética , Epigenoma , Tentativa de Suicídio , Estudo de Associação Genômica Ampla , Epigênese Genética , Metilação de DNARESUMO
A growing body of research has demonstrated the potential role for physical activity as an intervention across mental and other medical disorders. However, the association between physical activity and suicidal ideation, attempts, and deaths has not been systematically appraised in clinical samples. We conducted a PRISMA 2020-compliant systematic review searching MEDLINE, EMBASE, and PsycINFO for observational studies investigating the influence of physical activity on suicidal behavior up to December 6, 2023. Of 116 eligible full-text studies, seven (n = 141691) were included. Depression was the most frequently studied mental condition (43%, k = 3), followed by chronic pain as the most common other medical condition (29%, k = 2). Two case-control studies examined suicide attempts and found an association between physical activity and a reduced frequency of such attempts. However, in studies examining suicidal ideation (k = 3) or suicide deaths (k = 2), no consistent associations with physical activity were observed. Overall, our systematic review found that physical activity may be linked to a lower frequency of suicide attempts in non-prospective studies involving individuals with mental disorders.
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Exercício Físico , Transtornos Mentais , Estudos Observacionais como Assunto , Ideação Suicida , Tentativa de Suicídio , Humanos , Tentativa de Suicídio/estatística & dados numéricos , Tentativa de Suicídio/psicologia , Exercício Físico/fisiologia , Transtornos Mentais/psicologia , Transtornos Mentais/mortalidadeRESUMO
Aims: Social robots are arriving to the modern healthcare system. Whether patients with heart failure, a prevalent chronic disease with high health and human costs would derive benefit from a social robot intervention has not been investigated empirically. Diverse healthcare provider's perspectives are needed to develop an acceptable and feasible social robot intervention to be adopted for the clinical benefit of patients with heart failure. Using a qualitative research design, this study investigated healthcare providers' perspectives of social robot use in heart failure patient care. Methods and results: Interdisciplinary healthcare providers from a tertiary care cardiac hospital completed a structured individual interview and a supplemental questionnaire. The framework method was used to analyse the qualitative data. Respondents (n = 22; saturation was reached with this sample; 77% female; 52% physicians) were open to using social robots to augment their practice, particularly with collecting pertinent data and providing patient and family education and self-management prompts, but with limited responsibility for direct patient care. Prior to implementation, providers required robust evidence of: value-added beyond current remote patient monitoring devices, patient and healthcare provider partnerships, streamlined integration into existing practice, and capability of supporting precision medicine goals. Respondents were concerned that social robots did not address and masked broader systemic issues of healthcare access and equity. Conclusion: The adoption of social robots is a viable option to assist in the care of patients with heart failure, albeit in a restricted capacity. The results inform the development of a social robotic intervention for patients with heart failure, including improving social robot efficiencies and increasing their uptake, while protecting patients' and providers' best interest.
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BACKGROUND AND METHODS: We conducted a population-based, retrospective cohort study of first-time emergency department (ED) visits in adolescents and young adults (AYA) due to alcohol and compared mortality to AYA with nonalcohol ED visits between 2009 and 2015 using standardized all-cause mortality ratios (age, sex, income, and rurality). We described the cause of death for AYA and examined the association between clinical factors and mortality rates in the alcohol cohort using proportional hazard models. RESULTS: A total of 71,776 AYA had a first-time ED visit due to alcohol (56.1% male, mean age 20.7 years) between 2009 and 2015, representing 3.3% of the 2,166,838 AYA with an ED visit in this time period. At 1 year, there were 2396 deaths, 248 (10.3%) following an ED visit related to alcohol. First-time alcohol ED visits were associated with a threefold higher risk in mortality at 1 year (0.35% vs. 0.10%, adjusted hazard ratio [aHR] 3.07, 95% confidence interval [CI] 2.69-3.51). Mortality was associated with age 25-29 years (aHR 3.88, 95% CI 2.56-5.86), being male (aHR 1.98, 95% CI 1.49-2.62), having a history of mental health or substance use (aHR 3.22, 95% CI 1.64-6.32), cause of visit being withdrawal/dependence (aHR 2.81, 95% CI 1.96-4.02), and having recurrent ED visits (aHR 1.97, 95% CI 1.27-3.05). Trauma (42.7%), followed by poisonings from drugs other than opioids (38.3%), and alcohol (28.6%) were the most common contributing causes of death. CONCLUSION: Incident ED visits due to alcohol in AYA are associated with a high risk of 1-year mortality, especially in young adults, those with concurrent mental health or substance use disorders, and those with a more severe initial presentation. These findings may help inform the need and urgency for follow-up care in this population.