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.

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.

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.

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.

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.

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.

Problem gambling in psychotic disorders: A systematic review and meta-analysis of prevalence.

INTRODUCTION: Problem gambling (PBG) is more common in people with mental health disorders, including substance use, bipolar, and personality disorders, than in the general population. Although individuals with psychotic disorders might be expected to be more vulnerable to PBG, fewer studies have focused on this comorbidity. The aim of this review was to estimate the prevalence of PBG in people with psychotic disorders. METHODS: Medline (Ovid), EMBASE, PsycINFO (Ovid), CINAHL, CENTRAL, Web of science, and ProQuest were searched on November 1, 2023, without language restrictions. Observational and experimental studies including individuals with psychotic disorders and reporting the prevalence of PBG were included. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal for systematic reviews of prevalence data. The pooled prevalence of PBG was calculated using a fixed effects generalized linear mixed model and presented through forest plots. RESULTS: Of 1271 records screened, 12 studies (n = 3443) were included. The overall prevalence of PBG was 8.7% (95% CI = 7.8%-9.7%, I2 = 69%). A lower prevalence was found in studies with a low risk of bias (5.6%; 95% CI = 4.4%-7.0%) compared with studies with a moderate risk of bias (10.4%; 95% CI = 9.2%-11.7%). Different methods used to assess PBG also contributed to the heterogeneity found. CONCLUSION: This meta-analysis found substantial heterogeneity, partly due to the risk of bias of the included studies and a lack of uniformity in PBG assessment. Although more research is needed to identify those at increased risk for PBG, its relatively high prevalence warrants routine screening for gambling in clinical practice.

Effect and outcome of equity, diversity and inclusion programs in healthcare institutions: a systematic review protocol.

BACKGROUND: Equity, diversity and inclusion (EDI) in the healthcare field are crucial in meeting the healthcare needs of a progressively diverse society. In fact, a diverse healthcare workforce enables culturally sensitive care, promotes health equity and enhances the understanding of various needs and patients' viewpoints, potentially resulting in more effective patient treatment and improved patient outcomes. Despite this, information on the effectiveness of policies or programmes promoting EDI in health institutions is scarce. The objective of this systematic review is to assess the effects and outcomes of EDI programmes in healthcare institutions. METHODS: We will conduct Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review of studies on EDI programmes and describe their effects and outcomes in healthcare institutions. We will search PubMed, Scopus, Web of Science, CINAHL and PsycINFO databases. Selected studies will include randomised control trials (RCTs), non-RCTs and cross-sectional studies published either in English or French. Quality appraisal of studies and a narrative synthesis of extracted data will be conducted as well as a meta-analysis if possible. The quality of evidence in this review will be assessed by the Grades of Recommendation, Assessment, Development and Evaluation. ANTICIPATED RESULTS: We anticipate that this systematic review will reveal information on the effect of EDI programmes and their outcomes in healthcare institutions. We expect this information will provide insights that will lead to improvements in designing EDI policies and programmes in healthcare institutions. ETHICS AND DISSEMINATION: No ethical clearance is required for this study as no primary data will be collected. The final manuscript will be submitted to a journal for publication. In addition to this, the results of the study will also be disseminated through conference presentations to inform the research and clinical practice. REVIEW REGISTRATION: This protocol has been registered with the International Prospective Register of Systematic Reviews; registration number CRD42024502781.

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.

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.

Development of an anxiety disorder following an emergency department visit due to cannabis use: a population-based cohort study.

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.

Severe mental illness: cardiovascular risk assessment and management.

Patients with severe mental illness (SMI) including schizophrenia and bipolar disorder die on average 15-20 years earlier than the general population often due to sudden death that, in most cases, is caused by cardiovascular disease. This state-of-the-art review aims to address the complex association between SMI and cardiovascular risk, explore disparities in cardiovascular care pathways, describe how to adequately predict cardiovascular outcomes, and propose targeted interventions to improve cardiovascular health in patients with SMI. These patients have an adverse cardiovascular risk factor profile due to an interplay between biological factors such as chronic inflammation, patient factors such as excessive smoking, and healthcare system factors such as stigma and discrimination. Several disparities in cardiovascular care pathways have been demonstrated in patients with SMI, resulting in a 47% lower likelihood of undergoing invasive coronary procedures and substantially lower rates of prescribed standard secondary prevention medications compared with the general population. Although early cardiovascular risk prediction is important, conventional risk prediction models do not accurately predict long-term cardiovascular outcomes as cardiovascular disease and mortality are only partly driven by traditional risk factors in this patient group. As such, SMI-specific risk prediction models and clinical tools such as the electrocardiogram and echocardiogram are necessary when assessing and managing cardiovascular risk associated with SMI. In conclusion, there is a necessity for differentiated cardiovascular care in patients with SMI. By addressing factors involved in the excess cardiovascular risk, reconsidering risk stratification approaches, and implementing multidisciplinary care models, clinicians can take steps towards improving cardiovascular health and long-term outcomes in patients with SMI.

A state-of-the-art overview of candidate diagnostic biomarkers for Attention-deficit/hyperactivity disorder (ADHD).

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental conditions and is highly heterogeneous in terms of symptom profile, associated cognitive deficits, comorbidities, and outcomes. Heterogeneity may also affect the ability to recognize and diagnose this condition. The diagnosis of ADHD is primarily clinical but there are increasing research efforts aiming at identifying biomarkers that can aid the diagnosis. AREAS COVERED: We first discuss the definition of biomarkers and the necessary research steps from discovery to implementation. We then provide a broad overview of research studies on candidate diagnostic biomarkers in ADHD encompassing genetic/epigenetic, biochemical, neuroimaging, neurophysiological and neuropsychological techniques. Finally, we critically appraise current limitations in the field and suggest possible ways forward. EXPERT OPINION: Despite the large number of studies and variety of techniques used, no promising biomarkers have been identified so far. Clinical and biological heterogeneity as well as methodological limitations, including small sample size, lack of standardization, confounding factors, and poor replicability, have hampered progress in the field. Going forward, increased international collaborative efforts are warranted to support larger and more robustly designed studies, develop multimodal datasets to combine biomarkers and improve diagnostic accuracy, and ensure reproducibility and meaningful clinical translation.

Treatment and Mortality Following Cancer Diagnosis Among People With Non-affective Psychotic Disorders in Ontario, Canada: A Retrospective Cohort Study.

BACKGROUND AND HYPOTHESIS: People with psychotic disorders have a higher risk of mortality following cancer diagnosis, compared to people without psychosis. The extent to which this disparity is influenced by differences in cancer-related treatment is currently unknown. We hypothesized that, following a cancer diagnosis, people with psychotic disorders were less likely to receive treatment and were at higher risk of death than those without psychosis. STUDY DESIGN: We constructed a retrospective cohort of cases of non-affective psychotic disorder (NAPD) and a general population comparison group, using Ontario Health (OH) administrative data. We identified cases of all cancers diagnosed between 1995 and 2019 and obtained information on cancer-related treatment and mortality. Cox proportional hazards models were used to compare the probability of having a consultation with an oncologist and receiving cancer-related treatment, adjusting for tumor site and stage. We also compared the rate of all-cause and cancer-related mortality between the two groups, adjusting for tumor site. STUDY RESULTS: Our analytic sample included 24 944 people diagnosed with any cancer. People with NAPD were less likely to receive treatment than people without psychosis (HR = 0.87, 95% CI = 0.82, 0.91). In addition, people with NAPD had a greater risk of death from any cause (HR = 1.68, 95% CI = 1.60, 1.76), compared to people without NAPD. CONCLUSIONS: The lower likelihood of receiving cancer treatment reflects disparities in accessing cancer care for people with psychotic disorders, which may partially explain the higher mortality risk following cancer diagnosis. Future research should explore mediating factors in this relationship to identify targets for reducing health disparities.

Regional differences in mortality risk and in attenuating or aggravating factors in schizophrenia: A systematic review and meta-analysis.

People with schizophrenia die prematurely, yet regional differences are unclear. PRISMA 2020-compliant systematic review/random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) versus any control group, and moderators, in people with ICD/DSM-defined schizophrenia, comparing countries and continents. We conducted subgroup, meta-regression analyses, and quality assessment. The primary outcome was all-cause mortality. Secondary outcomes were suicide-, /natural-cause- and other-cause-related mortality. We included 135 studies from Europe (n = 70), North-America (n = 29), Asia (n = 33), Oceania (n = 2), Africa (n = 1). In incident plus prevalent schizophrenia, differences across continents emerged for all-cause mortality (highest in Africa, RR=5.98, 95 %C.I.=4.09-8.74, k = 1, lowest in North-America, RR=2.14, 95 %C.I.=1.92-2.38, k = 16), suicide (highest in Oceania, RR=13.5, 95 %C.I.=10.08-18.07, k = 1, lowest in North-America, RR=4.4, 95 %C.I.=4.07-4.76, k = 6), but not for natural-cause mortality. Europe had the largest association between antipsychotics and lower all-cause mortality/suicide (Asia had the smallest or no significant association, respectively), without differences for natural-cause mortality. Higher country socio-demographic index significantly moderated larger suicide-related and smaller natural-cause-related mortality risk in incident schizophrenia, with reversed associations in prevalent schizophrenia. Antipsychotics had a larger/smaller protective association in incident/prevalent schizophrenia regarding all-cause mortality, and smaller protective association for suicide-related mortality in prevalent schizophrenia. Additional regional differences emerged in incident schizophrenia, across countries, and secondary outcomes. Significant regional differences emerged for all-cause, cause-specific and suicide-related mortality. Natural-cause death was homogeneously increased globally. Moderators differed across countries. Global initiatives are needed to improve physical health in people with schizophrenia, local studies to identify actionable moderators.

Residual effects of medications for sleep disorders on driving performance: A systematic review and network meta-analysis of randomized controlled trials: NMA driving and hypnotics.

Sleep medications often carry residual effects potentially affecting driving safety, warranting network meta-analysis (NMA). PubMed/EMBASE/TRID/Clinicaltrials.gov/WHO-ICTRP/WebOfScience were inquired for randomized controlled trials of hypnotic driving studies in persons with insomnia and healthy subjects up to 05/28/2023, considering the vehicle's standard deviation of lateral position - SDLP (Standardized Mean Difference/SMD) and driving impairment rates on the first morning (co-primary outcomes) and endpoint. Risk-of-bias, global/local inconsistencies were measured, and CINeMA was used to assess the confidence in the evidence. Of 4,805 identified records, 26 cross-over RCTs were included in the systematic review, of which 22 entered the NMA, focusing on healthy subjects only. After a single administration, most molecules paralleled the placebo, outperforming zopiclone regarding SDLP. In contrast, ramelteon 8 mg, daridorexant 100 mg, zolpidem 10 mg bedtime, zolpidem middle-of-the-night 10 mg and 20 mg, mirtazapine 15-30 mg, and triazolam 0.5 mg performed significantly worse than placebo. Lemborexant 2.5-5 mg, suvorexant 15-20 mg, and zolpidem 3.5 mg middle-of-the-night associated with lower impairment than zopiclone. Repeated administration (maximum follow-up time of ten days) caused fewer residual effects than acute ones, except for flurazepam. Heterogeneity and inconsistency were negligible. Confidence in the evidence was low/very low. Sensitivity analyses confirmed the main analyses. Most FDA-approved hypnotics overlapped placebo at in-label doses, outperforming zopiclone. Repeated administration for 15 days or less reduced residual effects, warranting further research on the matter.

Health trends in Canada 1990-2019: An analysis for the Global Burden of Disease Study.

OBJECTIVE: Monitoring trends in key population health indicators is important for informing health policies. The aim of this study was to examine population health trends in Canada over the past 30 years in relation to other countries. METHODS: We used data on disability-adjusted life years (DALYs), years of life lost (YLL), years lived with disability, life expectancy (LE), and child mortality for Canada and other countries between 1990 and 2019 provided by the Global Burden of Disease Study. RESULTS: Life expectancy, age-standardized YLL, and age-standardized DALYs all improved in Canada between 1990 and 2019, although the rate of improvement has leveled off since 2011. The top five causes of all-age DALYs in Canada in 2019 were neoplasms, cardiovascular diseases, musculoskeletal disorders, neurological disorders, and mental disorders. The greatest increases in all-age DALYs since 1990 were observed for substance use, diabetes and chronic kidney disease, and sense organ disorders. Age-standardized DALYs declined for most conditions, except for substance use, diabetes and chronic kidney disease, and musculoskeletal disorders, which increased by 94.6%, 14.6%, and 7.3% respectively since 1990. Canada's world ranking for age-standardized DALYs declined from 9th place in 1990 to 24th in 2019. CONCLUSION: Canadians are healthier today than in 1990, but progress has slowed in Canada in recent years in comparison with other high-income countries. The growing burden of substance abuse, diabetes/chronic kidney disease, and musculoskeletal diseases will require continued action to improve population health.

RéSUMé: OBJECTIF: La surveillance des tendances des indicateurs clés de la santé de la population est importante pour éclairer les politiques de santé. Dans cette étude, nous avons examiné les tendances de la santé de la population au Canada au cours des 30 dernières années par rapport à d'autres pays. MéTHODES: Nous avons utilisé des données sur les années de vie ajustées en fonction de l'incapacité (DALY), les années de vie perdues (YLL), les années vécues avec un handicap, l'espérance de vie (LE) et la mortalité infantile pour le Canada et d'autres pays entre 1990 et 2019, fournies par l'Étude mondiale sur le fardeau de la maladie. RéSULTATS: L'espérance de vie, les YLL ajustées selon l'âge et les DALY ajustées selon l'âge ont tous connu une amélioration au Canada entre 1990 et 2019, bien que le taux d'amélioration se soit stabilisé depuis 2011. Les cinq principales causes des DALY pour tous les âges au Canada en 2019 étaient les néoplasmes, les maladies cardiovasculaires, les affections musculosquelettiques, les affections neurologiques et les troubles mentaux. Les plus fortes augmentations des DALY pour tous les âges depuis 1990 ont été observées pour l'usage de substances, le diabète et les maladies rénales chroniques, ainsi que les troubles des organes sensoriels. Les DALY ajustées selon l'âge ont diminué pour la plupart des conditions, à l'exception de l'usage de substances, du diabète et des maladies rénales chroniques, ainsi que des troubles musculosquelettiques, qui ont augmenté de 94,6 %, 14,6 % et 7,3 % respectivement depuis 1990. Le classement mondial du Canada pour les DALY ajustées selon l'âge est diminué de la 9ième place en 1990 à la 24ième place en 2019. CONCLUSION: Les Canadiens sont en meilleure santé aujourd'hui qu'en 1990, mais les progrès se sont ralentis ces dernières années par rapport à d'autres pays à revenu élevé. La croissance du fardeau lié à l'abus de substances, au diabète/maladies rénales chroniques et aux affections musculosquelettiques exigera des actions continues pour améliorer la santé de la population.

Racial and Ethnic Disparities in the Prescribing of Pain Medication in US Primary Care Settings, 1999-2019: Where Are We Now?

BACKGROUND: Policy initiatives have attempted to reduce healthcare inequalities in the USA, but evidence on whether these initiatives have reduced racial and ethnic disparities in pain treatment in primary care is lacking. OBJECTIVE: To determine whether racial and ethnic disparities in medication prescribed for pain in primary care settings have diminished over a 21-year period from 1999 to 2019. DESIGN: An annual, representative cross-sectional probability sample of visits to US primary care physicians, taken from the National Ambulatory Medical Care Survey. PATIENTS: Pain-related visits to primary care physicians. MAIN MEASURES: Prescriptions for opioid and non-opioid analgesics. KEY RESULTS: Of 599,293 (16%) sampled visits, 94,422 were pain-related, representing a population-weighted estimate of 143 million visits made annually to primary care physicians for pain. Relative risk analysis controlling for insurance, pain type, and other potential confounds showed no difference in pain medication prescribed between Black and White patients (p = .121). However, White patients were 1.61 (95% CI 1.32-1.97) and Black patients 1.57 (95% CI 1.26-1.95) times more likely to be prescribed opioids than a more underrepresented group consisting of Asian, Native-Hawaiian/Pacific-Islander, and American-Indian/Alaska-Natives (ps < .001). Non-Hispanic/Latino patients were 1.32 (95% CI 1.18-1.45) times more likely to receive opioids for pain than Hispanic/Latino patients (p < .001). Penalized cubic spline regression found no substantive narrowing of disparities over time. CONCLUSIONS: These findings suggest that additional intervention strategies, or better implementation of existing strategies, are needed to eliminate ethnic and racial disparities in pain treatment towards the goal of equitable healthcare.