Effects of antipsychotic treatment on cardio-cerebrovascular related mortality in schizophrenia: A subanalysis of a systematic review and meta-analysis with meta-regression of moderators.

To further explore the role of different antipsychotic treatments for cardio-cerebrovascular mortality, we performed several subgroup, sensitivity and meta-regression analyses based on a large previous meta-analysis focusing on cohort studies assessing mortality relative risk (RR) for cardio-cerebrovascular disorders in people with schizophrenia, comparing antipsychotic treatment versus no antipsychotic. Quality assessment through the Newcastle-Ottawa Scale (NOS) and publication bias was measured. We meta-analyzed 53 different studies (schizophrenia patients: n = 2,513,359; controls: n = 360,504,484) to highlight the differential effects of antipsychotic treatment regimens on cardio-cerebrovascular-related mortality in incident and prevalent samples of patients with schizophrenia. We found first generation antipsychotics (FGA) to be associated with higher mortality in incident samples of schizophrenia (oral FGA [RR=2.20, 95 %CI=1.29-3.77, k = 1] and any FGA [RR=1.70, 95 %CI=1.20-2.41, k = 1]). Conversely, second generation antipsychotics (SGAs) and clozapine were associated with reduced cardio-cerebrovascular-related mortality, in prevalent samples of schizophrenia. Subgroup analyses with NOS score ≥7 (higher quality) demonstrated a significantly increased cardio-cerebrovascular disorder-related mortality, among those exposed to FGAs vs SGAs. Meta-regression analyses demonstrated a larger association between antipsychotics and decreased risk of mortality with longer follow-up, recent study year, and higher number of adjustment variables. Overall, this subanalysis of a systematic review contributes to the evolving understanding of the complex role of antipsychotic treatment for cardio-cerebrovascular mortality in schizophrenia, paving the way for more targeted interventions and improved patient outcomes.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Inflammation is associated with a range of neuropsychiatric symptoms; however, the nature of the causal relationship is unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈ 55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning. Additionally, we examined the association between inflammatory GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (N max =57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (N max =23,268). In non-genetic analyses, higher CRP was associated with a depressive disorder, lower positive/higher negative affect, and worse executive function, attention, and psychomotor speed after adjusting for potential confounders. In genetic analyses, CRP GRS was associated with any anxiety disorder (ß = 0.002, p = 0.037) whereas GlycA GRS was associated with major depressive disorder (ß = 0.001, p = 0.036). Both CRP GRS (ß = 0.006, p = 0.035) and GlycA GRS (ß = 0.006, p = 0.049) were associated with greater negative affect. Inflammatory GRSs were not associated with cognition, except sIL-6R GRS which was associated with poorer memory (ß=-0.009, p = 0.018). There was weak evidence for a CRP-anxiety association using MR (ß = 0.12; p = 0.054). Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms.

Associations between autistic and comorbid somatic problems of gastrointestinal disorders, food allergy, pain, and fatigue in adults.

LAY ABSTRACT: What is already known about the topic?Autistic children frequently often have accompanying physical health problems. However, this has been much less studied in autistic men and women during adulthood.What does this article add?This is one of the first studies to investigate the associations between autistic and somatic problems in adults from the general population. Using a continuous measure of autistic symptom scores and a categorical definition of autism (referred to below as probable autism) which considered symptom severity, childhood age of onset, and functional impairment, we found that autistic problems and irritable bowel syndrome, food allergy, pain, and fatigue were associated in adults. Sex differences were present for pain and fatigue, for which the associations with autistic symptom scores were somewhat stronger in females than males. Regarding age differences, the associations with fatigue and having food allergy were more pronounced in younger adults. Conversely, older individuals had a higher risk of developing irritable bowel syndrome or experiencing pain if they met the criteria for probable autism.Implications for practice, research, or policyThere is a need for providing routine programs of screening, assessment, and treatment of autism-related somatic problems and developing evidence-based interventions for autistic individuals. These could be tailored to the needs of specific autistic populations. For example, autistic females could be given extra attention about the potential presence of pain and fatigue, younger adults about the potential presence of food allergy and fatigue, and older adults concerning the potential presence of irritable bowel syndrome and pain.

Somatic burden of attention-deficit/hyperactivity disorder across the lifecourse.

OBJECTIVE: A thorough and comprehensive knowledge base on the extent of comorbidity of attention-deficit/hyperactivity disorder (ADHD) and somatic conditions is needed. METHOD: We compared the prevalence of a wide range of somatic conditions in individuals with and without ADHD and described sex and lifecourse differences. Individuals with an ADHD diagnosis (N = 87,394) and age and sex-matched individuals without an ADHD diagnosis were identified from a large health claims dataset representative of the general German population, including both primary and specialized care (N = 4.874,754). Results were provided for the full sample as well as stratified for sex and age (<12 years, 13-17 years, 18-29 years, 30-59 years, ≥60 years). RESULTS: The results showed that ADHD is associated with a wide variety of somatic conditions across the entire lifecourse. Specifically neurological disorders such as Parkison's disease (odds ratio [OR]: 5.21) and dementia (OR: 2.23), sleep-related disorders (OR: 2.38) and autoimmune disorders affecting the musculoskeletal, digestive, and endocrine system (fibromyalgia OR: 3.33; lupus OR: 2.17) are strongly and significantly associated with ADHD. Additionally, ADHD is associated with higher occurrence of common acute diseases typically treated by the general practitioner, hinting at an overall general lower health status. Sex differences in somatic comorbidity were not prominent. Age differences, in contrast, stood out: in particular endocrine, cardiovascular, and neurological disorders had an early onset in individuals with compared to individuals without ADHD. CONCLUSION: This research underlines the high burden of disease due to somatic conditions among individuals with ADHD. The findings indicate the need for preventive measures to reduce comorbidity.

Patterns of sub-optimal change following CBT for childhood anxiety.

BACKGROUND: Children and adolescents demonstrate diverse patterns of symptom change and disorder remission following cognitive behavioural therapy (CBT) for anxiety disorders. To better understand children who respond sub-optimally to CBT, this study investigated youths (N = 1,483) who continued to meet criteria for one or more clinical anxiety diagnosis immediately following treatment or at any point during the 12 months following treatment. METHODS: Data were collected from 10 clinical sites with assessments at pre-and post-treatment and at least once more at 3, 6 or 12-month follow-up. Participants were assigned to one of three groups based on diagnostic status for youths who: (a) retained an anxiety diagnosis from post to end point (minimal responders); (b) remitted anxiety diagnoses at post but relapsed by end point (relapsed responders); and (c) retained a diagnosis at post but remitted to be diagnosis free at end point (delayed responders). Growth curve models assessed patterns of change over time for the three groups and examined predictors associated with these patterns including demographic, clinical and parental factors, as well as treatment factors. RESULTS: Higher primary disorder severity, being older, having a greater number of anxiety disorders, having social anxiety disorder, as well as higher maternal psychopathology differentiated the minimal responders from the delayed and relapsed responders at the baseline. Results from the growth curve models showed that severity of the primary disorder and treatment modality differentiated patterns of linear change only. Higher severity was associated with significantly less improvement over time for the minimal and relapsed response groups, as was receiving group CBT, when compared to the delayed response group. CONCLUSIONS: Sub-optimal response patterns can be partially differentiated using variables assessed at pre-treatment. Increased understanding of different patterns of change following treatment may provide direction for clinical decision-making and for tailoring treatments to specific groups of clinically anxious youth. Future research may benefit from assessing progress during treatment to detect emerging response patterns earlier.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Background: Low-grade systemic inflammation is implicated in the pathogenesis of various neuropsychiatric conditions affecting mood and cognition. While much of the evidence concerns depression, large-scale population studies of anxiety, affect, and cognitive function are scarce. Importantly, causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognitive performance in the Lifelines Cohort; and whether associations are likely to be causal. Methods: Using data from up to 55,098 (59% female) individuals from the Dutch Lifelines cohort, we tested the cross-sectional and longitudinal associations of C-reactive protein (CRP) with (i) depressive and anxiety disorders; (ii) positive and negative affect scores, and (iii) five cognitive measures assessing attention, psychomotor speed, episodic memory, and executive functioning (figural fluency and working memory). Additionally, we examined the association between inflammatory marker GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmax=57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmax=23,268). In genetic analyses, all GRSs and outcomes were z-transformed. Results: In non-genetic analyses, higher CRP was associated with diagnosis of any depressive disorder, lower positive and higher negative affect scores, and worse performance on tests of figural fluency, attention, and psychomotor speed after adjusting for potential confounders, although the magnitude of these associations was small. In genetic analyses, CRPGRS was associated with any anxiety disorder (ß=0.002, p=0.037, N=57,047) whereas GlycAGRS was associated with major depressive disorder (ß=0.001, p=0.036; N=57,047). Both CRPGRS (ß=0.006, p=0.035, N=57,946) and GlycAGRS (ß=0.006, p=0.049; N=57,946) were associated with higher negative affect score. Inflammatory marker GRSs were not associated with cognitive performance, except sIL-6RGRS which was associated with poorer memory performance (ß=-0.009, p=0.018, N=36,783). Further examination of the CRP-anxiety association using MR provided some weak evidence of causality (ß=0.12; p=0.054). Conclusions: Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. Genetic analyses suggest that IL-6 signaling could be relevant for memory, and that the association between CRP and anxiety disorders could be causal. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms. However, given the small effect sizes and multiple tests conducted, future studies are required to investigate whether effects are moderated by sub-groups and whether these findings replicate in other cohorts.

Longitudinal Measurement Invariance of the ASEBA Youth/Adult Self-Reports Across the Transition From Adolescence to Adulthood.

The ability to quantify within-person changes in mental health is central to the mission of clinical psychology. Typically, this is done using total or mean scores on symptom measures; however, this approach assumes that measures quantify the same construct, the same way, each time the measure is completed. Without this quality, termed longitudinal measurement invariance, an observed difference between timepoints might be partially attributable to changing measurement properties rather than changes in comparable symptom measurements. This concern is amplified in research using different forms of a measure across developmental periods due to potential differences in reporting styles, item-wording, and developmental context. This study provides the strongest support for the longitudinal measurement invariance of the Anxiety Scale, Depression/Affective Problems: Cognitive Subscale, and the Attention Deficit Hyperactivity Disorder (ADHD) Scale; moderate support for the Depression/Affective Problems Scale and the Somatic Scale, and poor support for the Depression/Affective Problems: Somatic Symptoms Subscale of the Dutch Achenbach System of Empirically Based Assessment Youth Self-Report and Adult Self-Report in a sample of 1,309 individuals (N = 1,090 population-based, N = 219 clinic-based/referred to an outpatient clinic before age 11 years) across six waves of data (mean ages = 11 years at Wave 1 and 26 years at Wave 6).

How a general vulnerability for psychopathology during adolescence manifests in young adults' daily lives.

BACKGROUND: There is widespread interest in the general factor of psychopathology or 'p factor', which has been proposed to reflect vulnerability to psychopathology. We examined to what extent this 'vulnerability' is associated with dysregulations in affect and behavior that occur in daily life. As such we hoped to provide an account of how this vulnerability may be maintained. METHODS: We used data from the Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2,772) collected at ages 11, 14, 16, 19, and 22 years to fit a bifactor model with a general psychopathology factor, alongside internalizing, externalizing (EXT), attention-deficit/hyperactivity, and autism spectrum problem domains. Following the fifth TRAILS assessment, a subsample of participants (n = 133, age = 22.6, 43% women) with heightened risk for psychopathology completed a 6-month daily diary protocol with one assessment each day. Using a dynamic structural equation approach, we examined to what extent mean intensity, variability, inertia, and within-day co-occurrence of EXT, anxious-tense, and depressed-withdrawn affects and behaviors were associated with general factor scores. RESULTS: Unexpectedly, higher general factor scores were not associated with higher mean intensity of any of the three types of daily negative affects and behaviors, but were associated with higher variability and less carryover (inertia) EXT affects and behaviors. CONCLUSIONS: We showed that individual differences in general factor scores do not manifest as differences in average levels of daily affects and behaviors, but instead were related to a type of EXT reactivity to the environment. Future research is necessary to investigate whether reactive irritable moods may be involved in or signal vulnerability sustained psychopathology.

The Mood and Resilience in Offspring (MARIO) project: a longitudinal cohort study among offspring of parents with and without a mood disorder.

BACKGROUND: One of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors. METHODS: MARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected. DISCUSSION: The MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.

Distal-to-proximal etiologically relevant variables associated with the general (p) and specific factors of psychopathology.

BACKGROUND: The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors. METHODS: Using data from four waves (ages 11-19) of TRAILS, we modeled a bifactor model of p and four specific factors [internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD)]. Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle. RESULTS: Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p's variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors [e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT)]. Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p. CONCLUSIONS: (1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.

Genomics Research of Lifetime Depression in the Netherlands: The BIObanks Netherlands Internet Collaboration (BIONIC) Project.

In this cohort profile article we describe the lifetime major depressive disorder (MDD) database that has been established as part of the BIObanks Netherlands Internet Collaboration (BIONIC). Across the Netherlands we collected data on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lifetime MDD diagnosis in 132,850 Dutch individuals. Currently, N = 66,684 of these also have genomewide single nucleotide polymorphism (SNP) data. We initiated this project because the complex genetic basis of MDD requires large population-wide studies with uniform in-depth phenotyping. For standardized phenotyping we developed the LIDAS (LIfetime Depression Assessment Survey), which then was used to measure MDD in 11 Dutch cohorts. Data from these cohorts were combined with diagnostic interview depression data from 5 clinical cohorts to create a dataset of N = 29,650 lifetime MDD cases (22%) meeting DSM-5 criteria and 94,300 screened controls. In addition, genomewide genotype data from the cohorts were assembled into a genomewide association study (GWAS) dataset of N = 66,684 Dutch individuals (25.3% cases). Phenotype data include DSM-5-based MDD diagnoses, sociodemographic variables, information on lifestyle and BMI, characteristics of depressive symptoms and episodes, and psychiatric diagnosis and treatment history. We describe the establishment and harmonization of the BIONIC phenotype and GWAS datasets and provide an overview of the available information and sample characteristics. Our next step is the GWAS of lifetime MDD in the Netherlands, with future plans including fine-grained genetic analyses of depression characteristics, international collaborations and multi-omics studies.

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.

Are Genetic and Environmental Risk Factors for Psychopathology Amplified in Children with Below-Average Intelligence? A Population-Based Twin Study.

There is a negative association between intelligence and psychopathology. We analyzed data on intelligence and psychopathology to assess this association in seven-year-old Dutch twin pairs (ranging from 616 to 14,150 depending on the phenotype) and estimated the degree to which genetic and environmental factors common to intelligence and psychopathology explain the association. Secondly, we examined whether genetic and environmental effects on psychopathology are moderated by intelligence. We found that intelligence, as assessed by psychometric IQ tests, correlated negatively with childhood psychopathology, as assessed by the DSM-oriented scales of the Child Behavior Check List (CBCL). The correlations ranged between - .09 and - .15 and were mainly explained by common genetic factors. Intelligence moderated genetic and environmental effects on anxiety and negative affect, but not those on ADHD, ODD, and autism. The heritability of anxiety and negative affect was greatest in individuals with below-average intelligence. We discuss mechanisms through which this effect could arise, and we end with some recommendations for future research.

Attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD; also known as hyperkinetic disorder) is a common neurodevelopmental condition that affects children and adults worldwide. ADHD has a predominantly genetic aetiology that involves common and rare genetic variants. Some environmental correlates of the disorder have been discovered but causation has been difficult to establish. The heterogeneity of the condition is evident in the diverse presentation of symptoms and levels of impairment, the numerous co-occurring mental and physical conditions, the various domains of neurocognitive impairment, and extensive minor structural and functional brain differences. The diagnosis of ADHD is reliable and valid when evaluated with standard diagnostic criteria. Curative treatments for ADHD do not exist but evidence-based treatments substantially reduce symptoms and/or functional impairment. Medications are effective for core symptoms and are usually well tolerated. Some non-pharmacological treatments are valuable, especially for improving adaptive functioning. Clinical and neurobiological research is ongoing and could lead to the creation of personalized diagnostic and therapeutic approaches for this disorder.

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Physical activity, suicidal ideation, suicide attempt and death among individuals with mental or other medical disorders: A systematic review of observational studies.

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.

ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases.

BACKGROUND: Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice. METHODS: We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available. FINDINGS: 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex. INTERPRETATION: Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use. FUNDING: European Union Horizon 2020 Research and Innovation Programme.

Mapping insomnia symptoms and circadian preferences to mental health problems in men and women across the lifespan.

This study identified subgroups in the general population based on combinations in three night-time insomnia symptoms and four dimensions of circadian preferences ("sleep profiles") and investigated the associations between sleep profiles and nine common mental health problems. The data came from the Lifelines cohort add-on study "Comorbid Conditions of ADHD" and included 37,716 individuals (aged 4-91 years) from the Dutch general population who completed a digital survey. Latent profile analysis was used to identify sleep profiles in twelve age-sex subgroups. Linear regression was used to investigate whether sleep profiles differ in mental health problems. Participants were classified into three sleep profiles: "Healthy Larks", who had early circadian preferences and no insomnia symptoms; "Sleepy Owls" with late circadian preferences and nonrestorative sleep; and "Sleepless Doves" with intermediate circadian preferences and severe insomnia symptoms. Compared to "Healthy Larks", all mental health problems were significantly more severe in "Sleepy Owls" and even worse in "Sleepless Doves". These associations were similar in men and women but weakened with age. However, "Sleepy Owls" and "Sleepless Doves" did not differ in heavy alcohol drinking, drug use, and smoking. Our findings strengthened the evidence for the universal role of healthy sleep in mental wellbeing.

Maternal Fiber Intake During Pregnancy and Development of Attention-Deficit/Hyperactivity Disorder Symptoms Across Childhood: The Norwegian Mother, Father, and Child Cohort Study.

BACKGROUND: Epidemiological studies suggest that maternal diet quality during pregnancy may influence the risk of neurodevelopmental disorders in offspring. Here, we investigated associations between maternal intake of dietary fiber and attention-deficit/hyperactivity disorder (ADHD) symptoms in early childhood. METHODS: We used longitudinal data of up to 21,852 mother-father-child trios (49.2% female offspring) from MoBa (the Norwegian Mother, Father, and Child Cohort Study). The relationships between maternal fiber intake during pregnancy and offspring ADHD symptoms at ages 3, 5, and 8 years were examined using 1) multivariate regression (overall levels of ADHD symptoms), 2) latent class analysis (subclasses of ADHD symptoms by sex at each age), and 3) latent growth curves (longitudinal change in offspring ADHD symptoms). Covariates were ADHD polygenic scores in child and parents, total energy intake and energy-adjusted sugar intake, parental ages at birth of the child, and sociodemographic factors. RESULTS: Higher maternal prenatal fiber intake was associated with lower offspring ADHD symptom scores at all ages (Bage3 = -0.14 [95% CI, -0.18 to -0.10]; Bage5 = -0.14 [95% CI, -0.19 to -0.09]; Bage8 = -0.14 [95% CI, -0.20 to -0.09]). Of the derived low/middle/high subclasses of ADHD symptoms, fiber was associated with lower risk of belonging to the middle subclass for boys and girls and to the high subclass for girls only (middle: odds ratioboys 0.91 [95% CI, 0.86 to 0.97]/odds ratiogirls 0.86 [95% CI, 0.81 to 0.91]; high: odds ratiogirls 0.82 [95% CI, 0.72 to 0.94]). Maternal fiber intake and rate of change in child ADHD symptoms across ages were not associated. CONCLUSIONS: Low prenatal maternal fiber intake may increase symptom levels of ADHD in offspring during childhood, independently of genetic predisposition to ADHD, unhealthy dietary exposures, and sociodemographic factors.