Treatments in the pipeline for attention-deficit/hyperactivity disorder (ADHD) in adults.

To provide an overview of treatments in the pipeline for adults with attention-deficit/hyperactivity disorder (ADHD), we searched https://clinicaltrials.gov/and and https://www.clinicaltrialsregister.eu/ from 01/01/2010-10/18/2023 for ongoing or completed phase 2 or 3 randomised controlled trials (RCTs), assessing pharmacological or non-pharmacological interventions for adults with ADHD with no current regulatory approval. We found 90 eligible RCTs. Of these, 24 (27 %) reported results with statistical analysis for primary efficacy endpoints. While several pharmacological and non-pharmacological interventions had evidence of superiority compared to the control condition from a single RCT, centanafadine (norepinephrine, dopamine, and serotonin re-uptake inhibitor) was the only treatment with evidence of efficacy on ADHD core symptoms (small effect size=0.28-0.40) replicated in at least one additional RCT, alongside reasonable tolerability. Overall, the body of ongoing RCTs in adults with ADHD is insufficient, without any intervention on the horizon to match the efficacy of stimulant treatment or atomoxetine and with better tolerability profile. Additional effective and well tolerated treatments for adults with ADHD require development and testing.

Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Clinical utility of the at-risk for psychosis state beyond transition: A multidimensional network analysis.

To be relevant to healthcare systems, the clinical high risk for psychosis (CHR-P) concept should denote a specific (i.e., unique) clinical population and provide useful information to guide the choice of intervention. The current study applied network analyses to examine the clinical specificities of CHR-P youths compared to general help-seekers and non-CHR-P youth. 146 CHR-P (mean age = 14.32 years) and 103 non-CHR-P (mean age = 12.58 years) help-seeking youth were recruited from a neuropsychiatric unit and assessed using the Structured Interview for Psychosis-Risk Syndromes, Children's Depression Inventory, Multidimensional Anxiety Scale for Children, Global Functioning: Social, Global Functioning: Role, and Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale. The first network structure comprised the entire help-seeking sample (i.e., help-seekers network), the second only CHR-P patients (i.e., CHR-P network), and the third only non-CHR-P patients (i.e., non-CHR-P network). In the help-seekers network, each variable presented at least one edge. In the CHR-P network, two isolated "archipelagos of symptoms" were identified: (a) a subgraph including functioning, anxiety, depressive, negative, disorganization, and general symptoms; and (b) a subgraph including positive symptoms and the intelligence quotient. In the non-CHR-P network, positive symptoms were negatively connected to functioning, disorganization, and negative symptoms. Positive symptoms were less connected in the CHR-P network, indicating a need for specific interventions alongside those treating comorbid disorders. The findings suggest specific clinical characteristics of CHR-P youth to guide the development of tailored interventions, thereby supporting the clinical utility of the CHR-P concept.

Psychosocial Interventions for Individuals With Comorbid Psychosis and Substance Use Disorders: Systematic Review and Meta-analysis of Randomized Studies.

BACKGROUND AND HYPOTHESIS: Substance use is highly prevalent among people with schizophrenia (SCZ) and related disorders, however, there is no broad-spectrum pharmacotherapy that concurrently addresses both addiction and psychotic symptoms. Psychosocial (PS) interventions, which have yielded promising results in treating psychosis and substance dependence separately, demonstrate potential but have not been systematically evaluated when combined. STUDY DESIGN: Systematic review and random-effects meta-analyses of randomized controlled trials (RCTs) investigating PS interventions for individuals with comorbid substance use and psychotic disorders, encompassing SCZ and schizophrenia spectrum disorders (SSD). We included relevant studies published from MEDLINE, PsycINFO, and Google Scholar through May 2023. STUDY RESULTS: We included 35 RCTs (5176 participants total; approximately 2840 with SSD). Intervention durations ranged from 30 min to 3 years. Meta-analysis did not identify a statistically significant pooled PS intervention effect on the main primary outcome, substance use (18 studies; 803 intervention, 733 control participants; standardized mean difference, -0.05 standard deviation [SD]; 95% CI, -0.16, 0.07 SD; I2 = 18%). PS intervention effects on other outcomes were also not statistically significant. Overall GRADE certainty of evidence was low. CONCLUSIONS: At present, the literature lacks sufficient evidence supporting the use of PS interventions as opposed to alternative therapeutic approaches for significantly improving substance use, symptomatology, or functioning in people with SCZ and related disorders. However, firm conclusions were precluded by low certainty of evidence. Further RCTs are needed to determine the efficacy of PS treatments for people with dual-diagnoses (DD), either alone or in combination with pharmacotherapy.

How to optimize the systematic review process using AI tools.

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.

On the value of meta-research for early career researchers: A commentary.

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.

Short- and long-term neuropsychiatric outcomes in long COVID in South Korea and Japan.

We investigated whether SARS-CoV-2 infection is associated with short- and long-term neuropsychiatric sequelae. We used population-based cohorts from the Korean nationwide cohort (discovery; n = 10,027,506) and the Japanese claims-based cohort (validation; n = 12,218,680) to estimate the short-term (<30 days) and long-term (≥30 days) risks of neuropsychiatric outcomes after SARS-CoV-2 infection compared with general population groups or external comparators (people with another respiratory infection). Using exposure-driven propensity score matching, we found that both the short- and long-term risks of developing neuropsychiatric sequelae were elevated in the discovery cohort compared with the general population and those with another respiratory infection. A range of conditions including Guillain-Barré syndrome, cognitive deficit, insomnia, anxiety disorder, encephalitis, ischaemic stroke and mood disorder exhibited a pronounced increase in long-term risk. Factors such as mild severity of COVID-19, increased vaccination against COVID-19 and heterologous vaccination were associated with reduced long-term risk of adverse neuropsychiatric outcomes. The time attenuation effect was the strongest during the first six months after SARS-CoV-2 infection, and this risk remained statistically significant for up to one year in Korea but beyond one year in Japan. The associations observed were replicated in the validation cohort. Our findings contribute to the growing evidence base on long COVID by considering ethnic diversity.

Protocol for the development of a reporting guideline for umbrella reviews on epidemiological associations using cross-sectional, case-control and cohort studies: the Preferred Reporting Items for Umbrella Reviews of Cross-sectional, Case-control and Cohort studies (PRIUR-CCC).

INTRODUCTION: Observational studies are fraught with several biases including reverse causation and residual confounding. Overview of reviews of observational studies (ie, umbrella reviews) synthesise systematic reviews with or without meta-analyses of cross-sectional, case-control and cohort studies, and may also aid in the grading of the credibility of reported associations. The number of published umbrella reviews has been increasing. Recently, a reporting guideline for overviews of reviews of healthcare interventions (Preferred Reporting Items for Overviews of Reviews (PRIOR)) was published, but the field lacks reporting guidelines for umbrella reviews of observational studies. Our aim is to develop a reporting guideline for umbrella reviews on cross-sectional, case-control and cohort studies assessing epidemiological associations. METHODS AND ANALYSIS: We will adhere to established guidance and prepare a PRIOR extension for systematic reviews of cross-sectional, case-control and cohort studies testing epidemiological associations between an exposure and an outcome, namely Preferred Reporting Items for Umbrella Reviews of Cross-sectional, Case-control and Cohort studies (PRIUR-CCC). Step 1 will be the project launch to identify stakeholders. Step 2 will be a literature review of available guidance to conduct umbrella reviews. Step 3 will be an online Delphi study sampling 100 participants among authors and editors of umbrella reviews. Step 4 will encompass the finalisation of PRIUR-CCC statement, including a checklist, a flow diagram, explanation and elaboration document. Deliverables will be (i) identifying stakeholders to involve according to relevant expertise and end-user groups, with an equity, diversity and inclusion lens; (ii) completing a narrative review of methodological guidance on how to conduct umbrella reviews, a narrative review of methodology and reporting in published umbrella reviews and preparing an initial PRIUR-CCC checklist for Delphi study round 1; (iii) preparing a PRIUR-CCC checklist with guidance after Delphi study; (iv) publishing and disseminating PRIUR-CCC statement. ETHICS AND DISSEMINATION: PRIUR-CCC has been approved by The Ottawa Health Science Network Research Ethics Board and has obtained consent (20220639-01H). Participants to step 3 will give informed consent. PRIUR-CCC steps will be published in a peer-reviewed journal and will guide reporting of umbrella reviews on epidemiological associations.

Efficacy and safety of long-acting injectable versus oral antipsychotics in the treatment of patients with early-phase schizophrenia-spectrum disorders: a systematic review and meta-analysis.

Background: Long-acting injectable antipsychotics (LAIs) have advantages over oral antipsychotics (OAPs) in preventing relapse and hospitalization in chronically ill patients with schizophrenia-spectrum disorders (SSDs), but evidence in patients with first-episode/recent-onset, that is, early-phase-SSDs is less clear. Objectives: To assess the relative medium- and long-term efficacy and safety of LAIs versus OAPs in the maintenance treatment of patients with early-phase SSDs. Method: We searched major electronic databases for head-to-head randomized controlled trials (RCTs) comparing LAIs and OAPs for the maintenance treatment of patients with early-phase-SSDs. Design: Pairwise, random-effects meta-analysis. Relapse/hospitalization and acceptability (all-cause discontinuation) measured at study-endpoint were co-primary outcomes, calculating risk ratios (RRs) with their 95% confidence intervals (CIs). Subgroup analyses sought to identify factors moderating differences in efficacy or acceptability between LAIs and OAPs. Results: Across 11 head-to-head RCTs (n = 2374, median age = 25.2 years, males = 68.4%, median illness duration = 45.8 weeks) lasting 13-104 (median = 78) weeks, no significant differences emerged between LAIs and OAPs for relapse/hospitalization prevention (RR = 0.79, 95%CI = 0.58-1.06, p = 0.13) and acceptability (RR = 0.92, 95%CI = 0.80-1.05, p = 0.20). The included trials were highly heterogeneous regarding methodology and patient populations. LAIs outperformed OAPs in preventing relapse/hospitalization in studies with stable patients (RR = 0.65, 95%CI = 0.45-0.92), pragmatic design (RR = 0.67, 95%CI = 0.54-0.82), and strict intent-to-treat approach (RR = 0.64, 95%CI = 0.52-0.80). Furthermore, LAIs were associated with better acceptability in studies with schizophrenia patients only (RR = 0.87, 95%CI = 0.79-0.95), longer illness duration (RR = 0.88, 95%CI = 0.80-0.97), unstable patients (RR = 0.89, 95%CI = 0.81-0.99) and allowed OAP supplementation of LAIs (RR = 0.90, 95%CI = 0.81-0.99). Conclusion: LAIs and OAPs did not differ significantly regarding relapse prevention/hospitalization and acceptability. However, in nine subgroup analyses, LAIs were superior to OAPs in patients with EP-SSDs with indicators of higher quality and/or pragmatic design regarding relapse/hospitalization prevention (four subgroup analyses) and/or reduced all-cause discontinuation (five subgroup analyses), without any instance of OAP superiority versus LAIs. More high-quality pragmatic trials comparing LAIs with OAPs in EP-SSDs are needed. Trial registration: CRD42023407120 (PROSPERO).

OBJECTIVE: We aimed to uncover whether LAIs or regular antipsychotic pills demonstrate better outcomes over the medium and long term for individuals in the early stages of schizophrenia. METHOD: We scrutinized several studies comparing LAIs to regular pills in treating early-stage schizophrenia. Employing a combined analysis, we assessed factors such as preventing relapses and hospitalizations, as well as patient treatment adherence. DESIGN: We combined different study results in one unique analysis. We delved into whether LAIs surpassed regular pills in preventing relapses and hospitalizations and in patient treatment adherence. RESULTS: In our study of 11 trials involving over 2000 participants, we observed that LAIs and regular antipsychotic pills were generally comparable regarding preventing relapses, hospitalizations, and treatment adherence. However, on closer inspection, LAIs appeared slightly more effective for specific groups in the early stages of schizophrenia. CONCLUSION: While LAIs and regular antipsychotic pills showed similar results for most individuals in the early stages of schizophrenia, our findings hint at the possibility that LAIs might have a slight edge for certain groups. Nevertheless, we emphasize the need for more high-quality studies to gain a clearer understanding. REGISTRATION: This study is registered under CRD42023407120 (PROSPERO).

Comparing long-acting injections and pills for early schizophrenia: a study review and combined analysis Background: We explored whether antipsychotics long-acting injections (LAIs) might outperform regular antipsychotics pills for people dealing with early-stage conditions like schizophrenia. While LAIs have clear benefits for those with long-term challenges, their effectiveness for those just starting to grapple with these issues is less certain.

Innova4Health: an integrated approach for prevention of recurrence and personalized treatment of Major Depressive Disorder.

Background: Major Depressive Disorder (MDD) is a prevalent mental health condition characterized by persistent low mood, cognitive and physical symptoms, anhedonia (loss of interest in activities), and suicidal ideation. The World Health Organization (WHO) predicts depression will become the leading cause of disability by 2030. While biological markers remain essential for understanding MDD's pathophysiology, recent advancements in social signal processing and environmental monitoring hold promise. Wearable technologies, including smartwatches and air purifiers with environmental sensors, can generate valuable digital biomarkers for depression assessment in real-world settings. Integrating these with existing physical, psychopathological, and other indices (autoimmune, inflammatory, neuroradiological) has the potential to improve MDD recurrence prevention strategies. Methods: This prospective, randomized, interventional, and non-pharmacological integrated study aims to evaluate digital and environmental biomarkers in adolescents and young adults diagnosed with MDD who are currently taking medication. The study implements a sensor-integrated platform built around an open-source "Pothos" air purifier system. This platform is designed for scalability and integration with third-party devices. It accomplishes this through software interfaces, a dedicated app, sensor signal pre-processing, and an embedded deep learning AI system. The study will enroll two experimental groups (10 adolescents and 30 young adults each). Within each group, participants will be randomly allocated to Group A or Group B. Only Group B will receive the technological equipment (Pothos system and smartwatch) for collecting digital biomarkers. Blood and saliva samples will be collected at baseline (T0) and endpoint (T1) to assess inflammatory markers and cortisol levels. Results: Following initial age-based stratification, the sample will undergo detailed classification at the 6-month follow-up based on remission status. Digital and environmental biomarker data will be analyzed to explore intricate relationships between these markers, depression symptoms, disease progression, and early signs of illness. Conclusion: This study seeks to validate an AI tool for enhancing early MDD clinical management, implement an AI solution for continuous data processing, and establish an AI infrastructure for managing healthcare Big Data. Integrating innovative psychophysical assessment tools into clinical practice holds significant promise for improving diagnostic accuracy and developing more specific digital devices for comprehensive mental health evaluation.

Changes associated with the COVID-19 pandemic on postpartum screening results in Ontario, Canada: The healthy babies healthy children screening tool.

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.

Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.

Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation Across Mental Disorders: A Systematic Review and Dose-Response Meta-Analysis.

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.

New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview.

Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.

Individualized prediction models in ADHD: a systematic review and meta-regression.

There have been increasing efforts to develop prediction models supporting personalised detection, prediction, or treatment of ADHD. We overviewed the current status of prediction science in ADHD by: (1) systematically reviewing and appraising available prediction models; (2) quantitatively assessing factors impacting the performance of published models. We did a PRISMA/CHARMS/TRIPOD-compliant systematic review (PROSPERO: CRD42023387502), searching, until 20/12/2023, studies reporting internally and/or externally validated diagnostic/prognostic/treatment-response prediction models in ADHD. Using meta-regressions, we explored the impact of factors affecting the area under the curve (AUC) of the models. We assessed the study risk of bias with the Prediction Model Risk of Bias Assessment Tool (PROBAST). From 7764 identified records, 100 prediction models were included (88% diagnostic, 5% prognostic, and 7% treatment-response). Of these, 96% and 7% were internally and externally validated, respectively. None was implemented in clinical practice. Only 8% of the models were deemed at low risk of bias; 67% were considered at high risk of bias. Clinical, neuroimaging, and cognitive predictors were used in 35%, 31%, and 27% of the studies, respectively. The performance of ADHD prediction models was increased in those models including, compared to those models not including, clinical predictors (ß = 6.54, p = 0.007). Type of validation, age range, type of model, number of predictors, study quality, and other type of predictors did not alter the AUC. Several prediction models have been developed to support the diagnosis of ADHD. However, efforts to predict outcomes or treatment response have been limited, and none of the available models is ready for implementation into clinical practice. The use of clinical predictors, which may be combined with other type of predictors, seems to improve the performance of the models. A new generation of research should address these gaps by conducting high quality, replicable, and externally validated models, followed by implementation research.

Interventions to prevent and treat delirium: An umbrella review of randomized controlled trials.

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.

Musculoskeletal morbidity in adults with spinal cord injuries: A nationwide cohort study.

BACKGROUND: An increase in the demand for quality of life following spinal cord injuries (SCIs) is associated with an increase in musculoskeletal (MSK) pain, highlighting the need for preventive measure research. OBJECTIVE: This study aimed to evaluate the incidence and hazards of MSK morbidities among Korean adults with SCIs, as well as the influence of SCI location on MSK morbidities. METHODS: Patient populations were selected from Korean National Health Insurance Service data (n = 276). The control group included individuals without SCIs (n = 10,000). We compared the incidences and determined the unadjusted and adjusted hazard ratios (HRs) of common MSK morbidities (osteoarthritis, connective tissue disorders, sarcopenia, myalgia, neuralgia, rheumatoid arthritis, myositis, and musculoskeletal infections) based on the location of injury (cervical, thoracic, or lumbar). RESULTS: Adults with SCIs had a higher incidence of MSK morbidity (48.45% vs. 36.6%) and a lower survival probability than those without SCIs. The incidence of MSK morbidity and survival probabilities were not significantly different for cervical cord injuries, whereas both measures were significantly different for thoracic and lumbar injuries. CONCLUSION: SCI increases the risk of MSK morbidity. Lumbar SCI is associated with a higher incidence and risk of MSK morbidity than are cervical or thoracic SCIs.

Antipsychotic Use and Risk of Breast Cancer in Women With Severe Mental Illness: Replication of a Nationwide Nested Case-Control Database Study.

BACKGROUND AND HYPOTHESIS: Breast cancer is more prevalent in women with severe mental illness than in the general population, and use of prolactin-increasing antipsychotics may be a contributing factor. STUDY DESIGN: A nested case-control study was conducted using the Swedish nationwide registers (inpatient/outpatient care, sickness absence, disability pension, prescribed drugs, cancers). All women aged 18-85 years with schizophrenia/schizoaffective/other nonaffective psychotic disorder/bipolar disorder and breast cancer (cases) were matched for age, primary psychiatric diagnosis, and disease duration with five women without cancer (controls). The association between cumulative exposure to prolactin-increasing/prolactin-sparing antipsychotics and breast cancer was analyzed using conditional logistic regression, adjusted for comorbidities and co-medications. STUDY RESULTS: Among 132 061 women, 1642 (1.24%) developed breast cancer between 2010 and 2021, at a mean age of 63.3 ±â€…11.8 years. Compared with 8173 matched controls, the odds of breast cancer increased in women with prior exposure to prolactin-increasing antipsychotics for 1-4 years (adjusted odds ratio [aOR] = 1.20, 95% confidence interval [CI] = 1.03-1.41), and for ≥ 5 years (aOR = 1.47, 95%CI = 1.26-1.71). There were no increased or decreased odds of breast cancer with exposure to prolactin-sparing antipsychotics of either 1-4 years (aOR = 1.17, 95%CI = 0.98-1.40) or ≥5 years (aOR = 0.99, 95%CI = 0.78-1.26). The results were consistent across all sensitivity analyses (ie, according to different age groups, cancer types, and primary psychiatric diagnosis). CONCLUSIONS: Although causality remains uncertain, exposure to prolactin-elevating antipsychotics for ≥ 1 year was associated with increased odds of breast cancer in women with severe mental illness. When prescribing antipsychotics, a shared decision-making process should consider individual risk factors for breast cancer.

Prenatal opioid exposure and subsequent risk of neuropsychiatric disorders in children: nationwide birth cohort study in South Korea.

OBJECTIVE: To investigate the potential association between prenatal opioid exposure and the risk of neuropsychiatric disorders in children. DESIGN: Nationwide birth cohort study. SETTING: From 1 January 2009 to 31 December 2020, birth cohort data of pregnant women in South Korea linked to their liveborn infants from the National Health Insurance Service of South Korea were collected. PARTICIPANTS: All 3 251 594 infants (paired mothers, n=2 369 322; age 32.1 years (standard deviation 4.2)) in South Korea from the start of 2010 to the end of 2017, with follow-up from the date of birth until the date of death or 31 December 2020, were included. MAIN OUTCOME MEASURES: Diagnosis of neuropsychiatric disorders in liveborn infants with mental and behaviour disorders (International Classification of Diseases 10th edition codes F00-99). Follow-up continued until the first diagnosis of neuropsychiatric disorder, 31 December 2020 (end of the study period), or the date of death, whichever occurred first. Eight cohorts were created: three cohorts (full unmatched, propensity score matched, and child screening cohorts) were formed, all of which were paired with sibling comparison cohorts, in addition to two more propensity score groups. Multiple subgroup analyses were performed. RESULTS: Of the 3 128 571 infants included (from 2 299 664 mothers), we identified 2 912 559 (51.3% male, 48.7% female) infants with no prenatal opioid exposure and 216 012 (51.2% male, 48.8% female) infants with prenatal opioid exposure. The risk of neuropsychiatric disorders in the child with prenatal opioid exposure was 1.07 (95% confidence interval 1.05 to 1.10) for fully adjusted hazard ratio in the matched cohort, but no significant association was noted in the sibling comparison cohort (hazard ratio 1.00 (0.93 to 1.07)). Prenatal opioid exposure during the first trimester (1.11 (1.07 to 1.15)), higher opioid doses (1.15 (1.09 to 1.21)), and long term opioid use of 60 days or more (1.95 (1.24 to 3.06)) were associated with an increased risk of neuropsychiatric disorders in the child. Prenatal opioid exposure modestly increased the risk of severe neuropsychiatric disorders (1.30 (1.15 to 1.46)), mood disorders, attention deficit hyperactivity disorder, and intellectual disability in the child. CONCLUSIONS: Opioid use during pregnancy was not associated with a substantial increase in the risk of neuropsychiatric disorders in the offspring. A slightly increased risk of neuropsychiatric disorders was observed, but this should not be considered clinically meaningful given the observational nature of the study, and limited to high opioid dose, more than one opioid used, longer duration of exposure, opioid exposure during early pregnancy, and only to some neuropsychiatric disorders.