Merete Nordentoft

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population. A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

<h2>Summary</h2> The unpredictability and uncertainty of the COVID-19 pandemic; the associated lockdowns, physical distancing, and other containment strategies; and the resulting economic breakdown could increase the risk of mental health problems and exacerbate health inequalities. Preliminary findings suggest adverse mental health effects in previously healthy people and especially in people with pre-existing mental health disorders. Despite the heterogeneity of worldwide health systems, efforts have been made to adapt the delivery of mental health care to the demands of COVID-19. Mental health concerns have been addressed via the public mental health response and by adapting mental health services, mostly focusing on infection control, modifying access to diagnosis and treatment, ensuring continuity of care for mental health service users, and paying attention to new cases of mental ill health and populations at high risk of mental health problems. Sustainable adaptations of delivery systems for mental health care should be developed by experts, clinicians, and service users, and should be specifically designed to mitigate disparities in health-care provision. Thorough and continuous assessment of health and service-use outcomes in mental health clinical practice will be crucial for defining which practices should be further developed and which discontinued. For this Position Paper, an international group of clinicians, mental health experts, and users of mental health services has come together to reflect on the challenges for mental health that COVID-19 poses. The interconnectedness of the world made society vulnerable to this infection, but it also provides the infrastructure to address previous system failings by disseminating good practices that can result in sustained, efficient, and equitable delivery of mental health-care delivery. Thus, the COVID-19 pandemic could be an opportunity to improve mental health services.

The mental health effects of the coronavirus disease 2019 (COVID-19) pandemic might be profound1Holmes EA O'Connor RC Perry VH et al.Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science.Lancet Psychiatry. 2020; (published online April 15.)https://doi.org/10.1016/S2215-0366(20)30168-1Summary Full Text Full Text PDF PubMed Scopus (3685) Google Scholar and there are suggestions that suicide rates will rise, although this is not inevitable. Suicide is likely to become a more pressing concern as the pandemic spreads and has longer-term effects on the general population, the economy, and vulnerable groups. Preventing suicide therefore needs urgent consideration. The response must capitalise on, but extend beyond, general mental health policies and practices. There is some evidence that deaths by suicide increased in the USA during the 1918–19 influenza pandemic2Wasserman IM The impact of epidemic, war, prohibition and media on suicide: United States, 1910–1920.Suicide Life Threat Behav. 1992; 22: 240-254PubMed Google Scholar and among older people in Hong Kong during the 2003 severe acute respiratory syndrome (SARS) epidemic.3Cheung YT Chau PH Yip PS A revisit on older adults suicides and severe acute respiratory syndrome (SARS) epidemic in Hong Kong.Int J Geriatr Psychiatry. 2008; 23: 1231-1238Crossref PubMed Scopus (285) Google Scholar The current context is different and evolving. A wide-ranging interdisciplinary response that recognises how the pandemic might heighten risk and applies knowledge about effective suicide prevention approaches is key. Selective, indicated, and universal interventions are required (figure). The likely adverse effects of the pandemic on people with mental illness, and on population mental health in general, might be exacerbated by fear, self-isolation, and physical distancing.4Yao H Chen JH Xu YF Patients with mental health disorders in the COVID-19 epidemic.Lancet Psychiatry. 2020; 7: e21Summary Full Text Full Text PDF PubMed Scopus (980) Google Scholar Suicide risk might be increased because of stigma towards individuals with COVID-19 and their families. Those with psychiatric disorders might experience worsening symptoms and others might develop new mental health problems, especially depression, anxiety, and post-traumatic stress (all associated with increased suicide risk). These mental health problems will be experienced by the general population and those with high levels of exposure to illness caused by COVID-19, such as frontline health-care workers and those who develop the illness. The consequences for mental health services are already being felt (eg, increased workloads and the need to find new ways of working). Some services are developing expertise in conducting psychiatric assessments and delivering interventions remotely (eg, by telephone or digitally); these new working practices should be implemented more widely, but with consideration that not all patients will feel comfortable with such interactions and they may present implications for privacy. Making evidence-based online resources and interventions freely available at scale could benefit population mental health. People in suicidal crises require special attention. Some might not seek help, fearing that services are overwhelmed and that attending face-to-face appointments might put them at risk. Others may seek help from voluntary sector crisis helplines which might be stretched beyond capacity due to surges in calls and reductions in volunteers. Mental health services should develop clear remote assessment and care pathways for people who are suicidal, and staff training to support new ways of working. Helplines will require support to maintain or increase their volunteer workforce, and offer more flexible methods of working. Digital training resources would enable those who have not previously worked with people who are suicidal to take active roles in mental health services and helplines. Evidence-based online interventions and applications should be made available to support people who are suicidal.5Torok M Han J Baker S et al.Suicide prevention using self-guided digital interventions: a systematic review and meta-analysis of randomised controlled trials.Lancet Digital Health. 2020; 2: e25-e36Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar Loss of employment and financial stressors are well-recognised risk factors for suicide.6Stuckler D Basu S Suhrcke M Coutts A McKee M The public health effect of economic crises and alternative policy responses in Europe: an empirical analysis.Lancet. 2009; 374: 315-323Summary Full Text Full Text PDF PubMed Scopus (1028) Google Scholar Governments should provide financial safety nets (eg, food, housing, and unemployment supports). Consideration must be given not only to individuals' current situations but also their futures. For example, many young people have had their education interrupted and are anxious about their prospects. Educational institutions must seek alternative ways to deliver curricula and governments need to be prepared to offer them financial support if necessary. Active labour market programmes will also be crucial.6Stuckler D Basu S Suhrcke M Coutts A McKee M The public health effect of economic crises and alternative policy responses in Europe: an empirical analysis.Lancet. 2009; 374: 315-323Summary Full Text Full Text PDF PubMed Scopus (1028) Google Scholar The pandemic could adversely affect other known precipitants of suicide. For example, domestic violence and alcohol consumption might increase during lockdown. Public health responses must ensure that those facing interpersonal violence are supported and that safe drinking messages are communicated. Social isolation, entrapment, and loneliness contribute to suicide risk7O'Connor RC Kirtley OJ The integrated motivational-volitional model of suicidal behaviour.Philos Trans R Soc Lond B Biol Sci. 2018; 37320170268Crossref PubMed Scopus (700) Google Scholar and are likely to increase during the pandemic, particularly for bereaved individuals. Providing community support for those living alone and encouraging families and friends to check in is helpful. Easily accessible help for bereaved individuals is crucial. Access to means is a major risk factor for suicide. In the current environment, certain lethal means (eg, firearms, pesticides, and analgesics) might be more readily available, stockpiled in homes. Retailers selling such products should be especially vigilant when dealing with distressed individuals. Governments and non-governmental organisations should consider temporary sales restrictions and deliver carefully framed messages about reducing access to commonly used and highly lethal suicide means. Irresponsible media reporting of suicide can lead to spikes in suicides.8Niederkrotenthaler T Braun M Pirkis J et al.Association between suicide reporting in the media and suicide: systematic review and meta-analysis.BMJ. 2020; 368: m575Crossref PubMed Scopus (186) Google Scholar Repeated exposure to stories about the crisis can increase fear9Garfin DR Silver RC Holman EA The novel coronavirus (COVID-2019) outbreak: amplification of public health consequences by media exposure.Health Psychol. 2020; (published online March 23.)DOI:10.1037/hea0000875Crossref PubMed Scopus (792) Google Scholar and heighten suicide risk. Media professionals should ensure that reporting follows existing10World Health OrganizationPreventing suicide: a resource for media professionals. Update 2017.https://www.who.int/mental_health/suicide-prevention/resource_booklet_2017/enDate accessed: March 4, 2020Google Scholar and COVID-19-specific guidelines. Comprehensive responses should be informed by enhanced surveillance of COVID-19-related risk factors contributing to suicidal behaviours. Some suicide and self-harm registers are now collecting data on COVID-19-related stressors contributing to the episode; summaries of these data will facilitate timely public health responses. Repeat representative cross-sectional and longitudinal surveys will help identify increases in population-level risk, as might anonymised real-time data on caller concerns from helplines. Monitoring demands and capacity of mental health-care providers over the coming months is also essential to ensure resources are directed to those parts of the system under greatest pressure. These efforts need to be appropriately resourced and coordinated. The suicide-related consequences of the pandemic might vary depending on countries' public health control measures, sociocultural and demographic structures, availability of digital alternatives to face-to-face consultation, and existing supports. The effects might be worse in resource-poor settings where economic adversity is compounded by inadequate welfare supports. Other concerns in these settings include social effects of banning religious gatherings and funerals, interpersonal violence, and vulnerable migrant workers. COVID-19-related stigma and misinformation may be particularly acute in these settings; many of the solutions proposed above will be applicable globally, but additional efforts will be required in resource-poor settings. These are unprecedented times. The pandemic will cause distress and leave many people vulnerable to mental health problems and suicidal behaviour. Mental health consequences are likely to be present for longer and peak later than the actual pandemic. However, research evidence and the experience of national strategies provide a strong basis for suicide prevention. We should be prepared to take the actions highlighted here, backed by vigilance and international collaboration. Affiliations of the International COVID-19 Suicide Prevention Research Collaboration are listed in the appendix. The views and recommendations in this Comment are endorsed by the International Association of Suicide Prevention, the American Foundation for Suicide Prevention, and the International Academy of Suicide Research. DG, KH, and NK are members of the Department of Health and Social Care (England) National Suicide Prevention Strategy Advisory Group; LA is the chair. DG has grants from the National Institute for Health Research (NIHR) outside the submitted work, and is a member of Samaritans Policy and Research Committee and Movember's Global Advisory Committee. LA and KH hold grants from the Department of Health and Social Care during the conduct of this work. AJ reports chairing the National Advisory Group on Suicide and Self-harm Prevention to Welsh Government and is national lead on suicide prevention for Public Health Wales. NK reports grants and personal fees from the Department of Health and Social Care, NIHR, National Institute of Health and Care Excellence (NICE), and Healthcare Quality and Improvement Partnership, outside the submitted work, and works with NHS England on national quality improvement. He has chaired NICE guideline committees for self-harm and depression and is currently the topic advisor for the new NICE guidelines for self-harm. RCO'C reports grants from NIHR, Medical Research Foundation, Scottish Government, NHS Health Scotland, and Public Health Scotland, outside the submitted work. He is also co-chair of the Academic Advisory Group to the Scottish Government's National Suicide Prevention Leadership Group, and a member of NICE's guideline development group for the new NICE guidelines for suicide and self-harm. All other authors declare no competing interests. Download .pdf (.14 MB) Help with pdf files Supplementary appendix Challenges facing individuals and researchers: suicide in India in the COVID-19 pandemicA recent article1 in a leading Indian newspaper, The Hindu, expressed concern about a potential rise in deaths by suicide during the COVID-19 pandemic. In this context, we were pleased to read the Comment by David Gunnell and colleagues2 in The Lancet Psychiatry, which emphasised the importance of identifying possible changes in the risk of suicide and acting towards its reduction by extending more help to people who are distressed. Full-Text PDF

Excess mortality among patients with severe mental disorders has not previously been investigated in detail in large complete national populations.To investigate the excess mortality in different diagnostic categories due to suicide and other external causes of death, and due to specific causes in connection with diseases and medical conditions.In longitudinal national psychiatric case registers from Denmark, Finland, and Sweden, a cohort of 270,770 recent-onset patients, who at least once during the period 2000 to 2006 were admitted due to a psychiatric disorder, were followed until death or the end of 2006. They were followed for 912,279 person years, and 28,088 deaths were analyzed. Life expectancy and standardized cause-specific mortality rates were estimated in each diagnostic group in all three countries.The life expectancy was generally approximately 15 years shorter for women and 20 years shorter for men, compared to the general population. Mortality due to diseases and medical conditions was increased two- to three-fold, while excess mortality from external causes ranged from three- to 77-fold. Mortality due to diseases and medical conditions was generally lowest in patients with affective disorders and highest in patients with substance abuse and personality disorders, while mortality due to suicide was highest in patients with affective disorders and personality disorders, and mortality due to other external causes was highest in patients with substance abuse.These alarming figures call for action in order to prevent the high mortality.

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

Background Several studies and meta-analyses have shown that mortality in people with schizophrenia is higher than that in the general population but have used relative measures, such as standardised mortality ratios. We did a systematic review and meta-analysis to estimate years of potential life lost and life expectancy in schizophrenia, which are more direct, absolute measures of increased mortality. Methods We searched MEDLINE, PsycINFO, Embase, Cinahl, and Web of Science for published studies on years of potential life lost and life expectancy in schizophrenia. Data from individual studies were combined in meta-analyses as weighted averages. We did subgroup analyses for sex, geographical region, timing of publication, and risk of bias (estimated with the Newcastle-Ottawa Scale). Findings We identified 11 studies in 13 publications covering all inhabited continents except South America (Africa n=1, Asia n=1, Australia n=1, Europe n=7, and North America n=3) that involved up to 247 603 patients. Schizophrenia was associated with a weighted average of 14·5 years of potential life lost (95% CI 11·2–17·8), and was higher for men than women (15·9, 13·8–18·0 vs 13·6, 11·4–15·8). Loss was least in the Asian study and greatest in Africa. The overall weighted average life expectancy was 64·7 years (95% CI 61·1–68·3), and was lower for men than women (59·9 years, 95% CI 55·5–64·3 vs 67·6 years, 63·1–72·1). Life expectancy was lowest in Asia and Africa. Timing of publication and risk of bias had little effect on results. Interpretation The effects of schizophrenia on years potential life lost and life expectancy seem to be substantial and not to have lessened over time. Development and implementation of interventions and initiatives to reduce this mortality gap are urgently needed. Funding None.

Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents.To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions.Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles.Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression.Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated.Depression scores after treatment and adverse effects.Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity.Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.

Schizophrenia is often referred to as one of the most severe mental disorders, primarily because of the very high mortality rates of those with the disorder. This article reviews the literature on excess early mortality in persons with schizophrenia and suggests reasons for the high mortality as well as possible ways to reduce it. Persons with schizophrenia have an exceptionally short life expectancy. High mortality is found in all age groups, resulting in a life expectancy of approximately 20 years below that of the general population. Evidence suggests that persons with schizophrenia may not have seen the same improvement in life expectancy as the general population during the past decades. Thus, the mortality gap not only persists but may actually have increased. The most urgent research agenda concerns primary candidates for modifiable risk factors contributing to this excess mortality, i.e., side effects of treatment and lifestyle factors, as well as sufficient prevention and treatment of physical comorbidity.

Excess mortality in persons with severe mental disorders (SMD) is a major public health challenge that warrants action. The number and scope of truly tested interventions in this area remain limited, and strategies for implementation and scaling up of programmes with a strong evidence base are scarce. Furthermore, the majority of available interventions focus on a single or an otherwise limited number of risk factors. Here we present a multilevel model highlighting risk factors for excess mortality in persons with SMD at the individual, health system and socio‐environmental levels. Informed by that model, we describe a comprehensive framework that may be useful for designing, implementing and evaluating interventions and programmes to reduce excess mortality in persons with SMD. This framework includes individual‐focused, health system‐focused, and community level and policy‐focused interventions. Incorporating lessons learned from the multilevel model of risk and the comprehensive intervention framework, we identify priorities for clinical practice, policy and research agendas.

Background: Persons with a history of admission to a psychiatric hospital are at high risk for suicide, but little is known about how this is influenced by factors related to psychiatric hospitalization.Objective: To explore suicide risk according to time since admission, diagnosis, length of hospital treatment, and number of prior hospitalizations.Design: Nested case-control design.Setting: Individual data are drawn from various Danish longitudinal registers.Participants: All 13 681 male and 7488 female suicides committed in Denmark from January 1, 1981, to December 31, 1997, and 423128 population control subjects matched for sex, age, and calendar time of suicide.Main Outcome Measure: Risk of suicide is estimated by conditional logistic regression.Data are adjusted for socioeconomic factors.Results: This study demonstrates that there are 2 sharp peaks of risk for suicide around psychiatric hospitaliza-tion, one in the first week after admission and another in the first week after discharge; suicide risk is significantly higher in patients who received less than the median duration of hospital treatment; affective disorders have the strongest impact on suicide risk in terms of its effect size and population attributable risk; and suicide risk associated with affective and schizophrenia spectrum disorders declines quickly after treatment and recovery, while the risk associated with substance abuse disorders declines relatively slower.This study also indicates that an admission history increases suicide risk relatively more in women than in men; and suicide risk is substantial for substance disorders and for multiple admissions in women but not in men.Conclusions: Suicide risk peaks in periods immediately after admission and discharge.The risk is particularly high in persons with affective disorders and in persons with short hospital treatment.These findings should lead to systematic evaluation of suicide risk among inpatients before discharge and corresponding outpatient treatment, and family support should be initiated immediately after the discharge.

Estimates of lifetime risk of suicide in mental disorders were based on selected samples with incomplete follow-up.To estimate, in a national cohort, the absolute risk of suicide within 36 years after the first psychiatric contact.Prospective study of incident cases followed up for as long as 36 years. Median follow-up was 18 years.Individual data drawn from Danish longitudinal registers.A total of 176,347 persons born from January 1, 1955, through December 31, 1991, were followed up from their first contact with secondary mental health services after 15 years of age until death, emigration, disappearance, or the end of 2006. For each participant, 5 matched control individuals were included.Absolute risk of suicide in percentage of individuals up to 36 years after the first contact.Among men, the absolute risk of suicide (95% confidence interval [CI]) was highest for bipolar disorder, (7.77%; 6.01%-10.05%), followed by unipolar affective disorder (6.67%; 5.72%-7.78%) and schizophrenia (6.55%; 5.85%-7.34%). Among women, the highest risk was found among women with schizophrenia (4.91%; 95% CI, 4.03%-5.98%), followed by bipolar disorder (4.78%; 3.48%-6.56%). In the nonpsychiatric population, the risk was 0.72% (95% CI, 0.61%-0.86%) for men and 0.26% (0.20%-0.35%) for women. Comorbid substance abuse and comorbid unipolar affective disorder significantly increased the risk. The co-occurrence of deliberate self-harm increased the risk approximately 2-fold. Men with bipolar disorder and deliberate self-harm had the highest risk (17.08%; 95% CI, 11.19%-26.07%).This is the first analysis of the absolute risk of suicide in a total national cohort of individuals followed up from the first psychiatric contact, and it represents, to our knowledge, the hitherto largest sample with the longest and most complete follow-up. Our estimates are lower than those most often cited, but they are still substantial and indicate the continuous need for prevention of suicide among people with mental disorders.

BackgroundInclusion health focuses on people in extremely poor health due to poverty, marginalisation, and multimorbidity. We aimed to review morbidity and mortality data on four overlapping populations who experience considerable social exclusion: homeless populations, individuals with substance use disorders, sex workers, and imprisoned individuals.MethodsFor this systematic review and meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library for studies published between Jan 1, 2005, and Oct 1, 2015. We included only systematic reviews, meta-analyses, interventional studies, and observational studies that had morbidity and mortality outcomes, were published in English, from high-income countries, and were done in populations with a history of homelessness, imprisonment, sex work, or substance use disorder (excluding cannabis and alcohol use). Studies with only perinatal outcomes and studies of individuals with a specific health condition or those recruited from intensive care or high dependency hospital units were excluded. We screened studies using systematic review software and extracted data from published reports. Primary outcomes were measures of morbidity (prevalence or incidence) and mortality (standardised mortality ratios [SMRs] and mortality rates). Summary estimates were calculated using a random effects model.FindingsOur search identified 7946 articles, of which 337 studies were included for analysis. All-cause standardised mortality ratios were significantly increased in 91 (99%) of 92 extracted datapoints and were 11·86 (95% CI 10·42–13·30; I2=94·1%) in female individuals and 7·88 (7·03–8·74; I2=99·1%) in men. Summary SMR estimates for the International Classification of Diseases disease categories with two or more included datapoints were highest for deaths due to injury, poisoning, and other external causes, in both men (7·89; 95% CI 6·40–9·37; I2=98·1%) and women (18·72; 13·73–23·71; I2=91·5%). Disease prevalence was consistently raised across the following categories: infections (eg, highest reported was 90% for hepatitis C, 67 [65%] of 103 individuals for hepatitis B, and 133 [51%] of 263 individuals for latent tuberculosis infection), mental health (eg, highest reported was 9 [4%] of 227 individuals for schizophrenia), cardiovascular conditions (eg, highest reported was 32 [13%] of 247 individuals for coronary heart disease), and respiratory conditions (eg, highest reported was 9 [26%] of 35 individuals for asthma).InterpretationOur study shows that homeless populations, individuals with substance use disorders, sex workers, and imprisoned individuals experience extreme health inequities across a wide range of health conditions, with the relative effect of exclusion being greater in female individuals than male individuals. The high heterogeneity between studies should be explored further using improved data collection in population subgroups. The extreme health inequity identified demands intensive cross-sectoral policy and service action to prevent exclusion and improve health outcomes in individuals who are already marginalised.FundingWellcome Trust, National Institute for Health Research, NHS England, NHS Research Scotland Scottish Senior Clinical Fellowship, Medical Research Council, Chief Scientist Office, and the Central and North West London NHS Trust.

To evaluate the effects of integrated treatment for patients with a first episode of psychotic illness.Randomised clinical trial.Copenhagen Hospital Corporation and Psychiatric Hospital Aarhus, Denmark.547 patients with first episode of schizophrenia spectrum disorder.Integrated treatment and standard treatment. The integrated treatment lasted for two years and consisted of assertive community treatment with programmes for family involvement and social skills training. Standard treatment offered contact with a community mental health centre.Psychotic and negative symptoms (each scored from 0 to a maximum of 5) at one and two years' follow-up.At one year's follow-up, psychotic symptoms changed favourably to a mean of 1.09 (standard deviation 1.27) with an estimated mean difference between groups of -0.31 (95% confidence interval -0.55 to -0.07, P = 0.02) in favour of integrated treatment. Negative symptoms changed favourably with an estimated difference between groups of -0.36 (-0.54 to -0.17, P < 0.001) in favour of integrated treatment. At two years' follow-up the estimated mean difference between groups in psychotic symptoms was -0.32 (-0.58 to -0.06, P = 0.02) and in negative symptoms was -0.45 (-0.67 to -0.22, P < 0.001), both in favour of integrated treatment. Patients who received integrated treatment had significantly less comorbid substance misuse, better adherence to treatment, and more satisfaction with treatment.Integrated treatment improved clinical outcome and adherence to treatment. The improvement in clinical outcome was consistent at one year and two year follow-ups.

<h3>Importance</h3> The value of early intervention in psychosis and allocation of public resources has long been debated because outcomes in people with schizophrenia spectrum disorders have remained suboptimal. <h3>Objective</h3> To compare early intervention services (EIS) with treatment as usual (TAU) for early-phase psychosis. <h3>Data Sources</h3> Systematic literature search of PubMed, PsycINFO, EMBASE, and ClinicalTrials.gov without language restrictions through June 6, 2017. <h3>Study Selection</h3> Randomized trials comparing EIS vs TAU in first-episode psychosis or early-phase schizophrenia spectrum disorders. <h3>Data Extraction and Synthesis</h3> This systematic review was conducted according to PRISMA guidelines. Three independent investigators extracted data for a random-effects meta-analysis and prespecified subgroup and meta-regression analyses. <h3>Main Outcomes and Measures</h3> The coprimary outcomes were all-cause treatment discontinuation and at least 1 psychiatric hospitalization during the treatment period. <h3>Results</h3> Across 10 randomized clinical trials (mean [SD] trial duration, 16.2 [7.4] months; range, 9-24 months) among 2176 patients (mean [SD] age, 27.5 [4.6] years; 1355 [62.3%] male), EIS was associated with better outcomes than TAU at the end of treatment for all 13 meta-analyzable outcomes. These outcomes included the following: all-cause treatment discontinuation (risk ratio [RR], 0.70; 95% CI, 0.61-0.80;<i>P</i> &lt; .001), at least 1 psychiatric hospitalization (RR, 0.74; 95% CI, 0.61-0.90;<i>P</i> = .003), involvement in school or work (RR, 1.13; 95% CI, 1.03-1.24;<i>P</i> = .01), total symptom severity (standardized mean difference [SMD], −0.32; 95% CI, −0.47 to −0.17;<i>P</i> &lt; .001), positive symptom severity (SMD, −0.22; 95% CI, −0.32 to −0.11;<i>P</i> &lt; .001), and negative symptom severity (SMD, −0.28; 95% CI, −0.42 to −0.14;<i>P</i> &lt; .001). Superiority of EIS regarding all outcomes was evident at 6, 9 to 12, and 18 to 24 months of treatment (except for general symptom severity and depressive symptom severity at 18-24 months). <h3>Conclusions and Relevance</h3> In early-phase psychosis, EIS are superior to TAU across all meta-analyzable outcomes. These results support the need for funding and use of EIS in patients with early-phase psychosis.

The COVID-19 pandemic is having profound mental health consequences for many people. Concerns have been expressed that, at their most extreme, these consequences could manifest as increased suicide rates. We aimed to assess the early effect of the COVID-19 pandemic on suicide rates around the world.We sourced real-time suicide data from countries or areas within countries through a systematic internet search and recourse to our networks and the published literature. Between Sept 1 and Nov 1, 2020, we searched the official websites of these countries' ministries of health, police agencies, and government-run statistics agencies or equivalents, using the translated search terms "suicide" and "cause of death", before broadening the search in an attempt to identify data through other public sources. Data were included from a given country or area if they came from an official government source and were available at a monthly level from at least Jan 1, 2019, to July 31, 2020. Our internet searches were restricted to countries with more than 3 million residents for pragmatic reasons, but we relaxed this rule for countries identified through the literature and our networks. Areas within countries could also be included with populations of less than 3 million. We used an interrupted time-series analysis to model the trend in monthly suicides before COVID-19 (from at least Jan 1, 2019, to March 31, 2020) in each country or area within a country, comparing the expected number of suicides derived from the model with the observed number of suicides in the early months of the pandemic (from April 1 to July 31, 2020, in the primary analysis).We sourced data from 21 countries (16 high-income and five upper-middle-income countries), including whole-country data in ten countries and data for various areas in 11 countries). Rate ratios (RRs) and 95% CIs based on the observed versus expected numbers of suicides showed no evidence of a significant increase in risk of suicide since the pandemic began in any country or area. There was statistical evidence of a decrease in suicide compared with the expected number in 12 countries or areas: New South Wales, Australia (RR 0·81 [95% CI 0·72-0·91]); Alberta, Canada (0·80 [0·68-0·93]); British Columbia, Canada (0·76 [0·66-0·87]); Chile (0·85 [0·78-0·94]); Leipzig, Germany (0·49 [0·32-0·74]); Japan (0·94 [0·91-0·96]); New Zealand (0·79 [0·68-0·91]); South Korea (0·94 [0·92-0·97]); California, USA (0·90 [0·85-0·95]); Illinois (Cook County), USA (0·79 [0·67-0·93]); Texas (four counties), USA (0·82 [0·68-0·98]); and Ecuador (0·74 [0·67-0·82]).This is the first study to examine suicides occurring in the context of the COVID-19 pandemic in multiple countries. In high-income and upper-middle-income countries, suicide numbers have remained largely unchanged or declined in the early months of the pandemic compared with the expected levels based on the pre-pandemic period. We need to remain vigilant and be poised to respond if the situation changes as the longer-term mental health and economic effects of the pandemic unfold.None.

Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.

People with mental disorders evince excess mortality due to natural and unnatural deaths. The relative life expectancy of people with mental disorders is a proxy measure of effectiveness of social policy and health service provision.To evaluate trends in health outcomes of people with serious mental disorders.We examined nationwide 5-year consecutive cohorts of people admitted to hospital for mental disorders in Denmark, Finland and Sweden in 1987-2006. In each country the risk population was identified from hospital discharge registers and mortality data were retrieved from cause-of-death registers. The main outcome measure was life expectancy at age 15 years.People admitted to hospital for a mental disorder had a two- to threefold higher mortality than the general population in all three countries studied. This gap in life expectancy was more pronounced for men than for women. The gap decreased between 1987 and 2006 in these countries, especially for women. The notable exception was Swedish men with mental disorders. In spite of the positive general trend, men with mental disorders still live 20 years less, and women 15 years less, than the general population.During the era of deinstitutionalisation the life expectancy gap for people with mental disorders has somewhat diminished in the three Nordic countries. Our results support further development of the Nordic welfare state model, i.e. tax-funded community-based public services and social protection. Health promotion actions, improved access to healthcare and prevention of suicides and violence are needed to further reduce the life expectancy gap.

Objective: Autoimmune diseases have been associated with an increased risk of schizophrenia. It has been suggested that brain-reactive autoantibodies are part of the mechanisms behind this association. Furthermore, an increased permeability of the blood-brain barrier has been observed during periods of infection and inflammation. The authors therefore investigated whether autoimmune diseases combined with exposures to severe infections may increase the risk of schizophrenia Method: Nationwide population-based registers in Denmark were linked, and the data were analyzed in a cohort study using survival analysis. All analyses were adjusted for calendar year, age, and sex. Incidence rate ratios and accompanying 95% confidence intervals (CIs) as measures of relative risk were used. Results: A prior autoimmune disease increased the risk of schizophrenia by 29% (incidence rate ratio=1.29; 95% CI=1.18–1.41). Any history of hospitalization with infection increased the risk of schizophrenia by 60% (incidence rate ratio=1.60; 95% CI=1.56–1.64). When the two risk factors were combined, the risk of schizophrenia was increased even further (incidence rate ratio=2.25; 95% CI=2.04–2.46). The risk of schizophrenia was increased in a dose-response relationship, where three or more infections and an autoimmune disease were associated with an incidence rate ratio of 3.40 (95% CI=2.91–3.94). The results remained significant after adjusting for substance use disorders and family history of psychiatric disorders. Hospital contact with infection occurred in nearly 24% of individuals prior to a schizophrenia diagnosis. Conclusions: Autoimmune disease and the number of infections requiring hospitalization are risk factors for schizophrenia. The increased risk is compatible with an immunological hypothesis in subgroups of schizophrenia patients.

Twin studies have provided evidence that both genetic and environmental factors contribute to schizophrenia (SZ) risk. Heritability estimates of SZ in twin samples have varied methodologically. This study provides updated heritability estimates based on nationwide twin data and an improved statistical methodology.Combining two nationwide registers, the Danish Twin Register and the Danish Psychiatric Research Register, we identified a sample of twins born between 1951 and 2000 (N = 31,524 twin pairs). Twins were followed until June 1, 2011. Liability threshold models adjusting for censoring with inverse probability weighting were used to estimate probandwise concordance rates and heritability of the diagnoses of SZ and SZ spectrum disorders.The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. We estimated the heritability of SZ to be 79%. When expanding illness outcome to include SZ spectrum disorders, the heritability estimate was almost similar (73%).The key strength of this study is the application of a novel statistical method accounting for censoring in the follow-up period to a nationwide twin sample. The estimated 79% heritability of SZ is congruent with previous reports and indicates a substantial genetic risk. The high genetic risk also applies to a broader phenotype of SZ spectrum disorders. The low concordance rate of 33% in monozygotic twins demonstrates that illness vulnerability is not solely indicated by genetic factors.

Intensive early treatment for first-episode psychosis has been shown to be effective. It is unknown if the positive effects are sustained for 5 years.To determine the long-term effects of an intensive early-intervention program (OPUS) for first-episode psychotic patients.Single-blinded, randomized, controlled clinical trial of 2 years of an intensive early-intervention program vs standard treatment. Follow-up periods were 2 and 5 years.Copenhagen Hospital Corporation and Psychiatric Hospital, Aarhus, Denmark. Patients A total of 547 patients with a first episode of psychosis. Of these, 369 patients were participating in a 2-year follow-up, and 301 were participating in a 5-year follow-up. A total of 547 patients were followed for 5 years.Two years of an intensive early-intervention program vs standard treatment. The intensive early-intervention treatment consisted of assertive community treatment, family involvement, and social skills training. Standard treatment offered contact with a community mental health center.Psychotic and negative symptoms were recorded. Secondary outcome measures were use of services and social functioning.Analysis was based on the principles of intention-to-treat. Assessment was blinded for previous treatment allocation. At the 5-year follow-up, the effect of treatment seen after 2 years (psychotic dimension odds ratio [OR], -0.32; 95% confidence interval [CI], -0.58 to -0.06; P = .02; negative dimension OR, -0.45; 95% CI, -0.67 to -0.22; P = .001) had equalized between the treatment groups. A significantly smaller percentage of patients from the experimental group were living in supported housing (4% vs 10%, respectively; OR, 2.3; 95% CI, 1.1-4.8; P = .02) and were hospitalized fewer days (mean, 149 vs 193 days; mean difference, 44 days; 95% CI, 0.15-88.12; P = .05) during the 5-year period.The intensive early-intervention program improved clinical outcome after 2 years, but the effects were not sustainable up to 5 years later. Secondary outcome measures showed differences in the proportion of patients living in supported housing and days in hospital at the 5-year follow-up in favor of the intensive early-intervention program.

Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking.To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders.Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex.Individual data drawn from Danish longitudinal registers.A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91, 637 people having hospital contacts for mood disorders.The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk.A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, 1.39-1.52). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, 1.60-1.64). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, 2.25-2.46). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease.Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients.

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

This guidance paper from the European Psychiatric Association (EPA) aims to provide evidence-based recommendations on early intervention in clinical high risk (CHR) states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. Besides analyses on treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n=1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional improvements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates, but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples could have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk status.

<h3>Importance</h3> Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. <h3>Objectives</h3> To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. <h3>Design, Setting, and Participants</h3> This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. <h3>Main Outcomes and Measures</h3> Danish health registers were used to identify mental disorders, which were examined within the broad 10-level<i>International Statistical Classification of Diseases and Related Health Problems, 10th Revision</i>, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. <h3>Results</h3> A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). <h3>Conclusions and Relevance</h3> Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

Systematic reviews have consistently shown that individuals with mental disorders have an increased risk of premature mortality. Traditionally, this evidence has been based on relative risks or crude estimates of reduced life expectancy. The aim of this study was to compile a comprehensive analysis of mortality-related health metrics associated with mental disorders, including sex-specific and age-specific mortality rate ratios (MRRs) and life-years lost (LYLs), a measure that takes into account age of onset of the disorder.In this population-based cohort study, we included all people younger than 95 years of age who lived in Denmark at some point between Jan 1, 1995, and Dec 31, 2015. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and the date and cause of death was obtained from the Danish Register of Causes of Death. We classified mental disorders into ten groups and causes of death into 11 groups, which were further categorised into natural causes (deaths from diseases and medical conditions) and external causes (suicide, homicide, and accidents). For each specific mental disorder, we estimated MRRs using Poisson regression models, adjusting for sex, age, and calendar time, and excess LYLs (ie, difference in LYLs between people with a mental disorder and the general population) for all-cause mortality and for each specific cause of death.7 369 926 people were included in our analysis. We found that mortality rates were higher for people with a diagnosis of a mental disorder than for the general Danish population (28·70 deaths [95% CI 28·57-28·82] vs 12·95 deaths [12·93-12·98] per 1000 person-years). Additionally, all types of disorders were associated with higher mortality rates, with MRRs ranging from 1·92 (95% CI 1·91-1·94) for mood disorders to 3·91 (3·87-3·94) for substance use disorders. All types of mental disorders were associated with shorter life expectancies, with excess LYLs ranging from 5·42 years (95% CI 5·36-5·48) for organic disorders in females to 14·84 years (14·70-14·99) for substance use disorders in males. When we examined specific causes of death, we found that males with any type of mental disorder lost fewer years due to neoplasm-related deaths compared with the general population, although their cancer mortality rates were higher.Mental disorders are associated with premature mortality. We provide a comprehensive analysis of mortality by different types of disorders, presenting both MRRs and premature mortality based on LYLs, displayed by age, sex, and cause of death. By providing accurate estimates of premature mortality, we reveal previously underappreciated features related to competing risks and specific causes of death.Danish National Research Foundation.

Article Abstract Context: Persons suffering from severe mental disorder have an excess mortality compared to persons with no mental disorder. However, the magnitude of the excess mortality differs from one mental disorder to another, and the impact on mortality if a first-degree family member suffers from a mental disorder has never been examined in a population-based study. Objective: Our objective was to examine and compare mortality rates after admission with schizophrenia, schizoaffective disorder, unipolar depressive disorder, or bipolar affective disorder and to examine the impact of family history of psychiatric admission on mortality. Method: We established a register-based cohort study of 5.5 million persons born in Denmark who were alive on or born after January 1, 1973 and alive on their 15th birthday. Mortality rate ratios were estimated by survival analysis, using Poisson regression. Results: Unipolar depressive disorder, bipolar affective disorder, and schizoaffective disorder were associated with the same pattern of excess mortality. Schizophrenia had a lower mortality from unnatural causes of death and a higher mortality from natural causes compared to the 3 other disorders. Family history of psychiatric admission was associated with excess mortality. Conclusion: Patients suffering from the 4 disorders all had an excess mortality, but the pattern of excess mortality was not the same. There was an excess mortality associated with mental disorder in a first-degree family member, but this only explained a small part of the general excess mortality associated with the 4 mental disorders examined.

Abstract The aim of this guidance paper of the European Psychiatric Association is to provide evidence-based recommendations on the early detection of a clinical high risk (CHR) for psychosis in patients with mental problems. To this aim, we conducted a meta-analysis of studies reporting on conversion rates to psychosis in non-overlapping samples meeting any at least any one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria. Further, effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates were examined. Conversion rates in the identified 42 samples with altogether more than 4000 CHR patients who had mainly been identified by UHR criteria and/or the basic symptom criterion ‘cognitive disturbances’ (COGDIS) showed considerable heterogeneity. While UHR criteria and COGDIS were related to similar conversion rates until 2-year follow-up, conversion rates of COGDIS were significantly higher thereafter. Differences in onset and frequency requirements of symptomatic UHR criteria or in their different consideration of functional decline, substance use and co-morbidity did not seem to impact on conversion rates. The ‘genetic risk and functional decline’ UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for an early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states.

To assess the effectiveness of exercise in adults with clinical depression.The databases CINAHL, Embase, Cochrane Database of Systematic reviews, Cochrane Controlled Trials Register, MEDLINE, and PsycINFO were searched (1806-2008) using medical subject headings (MeSH) and text word terms depression, depressive disorder and exercise, aerobic, non-aerobic, physical activity, physical fitness, walk*, jog*, run*, bicycling, swim*, strength, and resistance.Randomized trials including adults with clinical depression according to any diagnostic system were included.Two investigators evaluated trials using a prepiloted structured form.Thirteen trials were identified that fulfilled the inclusion criteria. Eight had adequate allocation concealment, 6 had a blinded outcome, and 5 used intention-to-treat analyses. The pooled standardized mean difference (SMD) calculated using a random-effects model was -0.40 (95% CI, -0.66 to -0.14), with evidence of heterogeneity between trials (I(2) = 57.2%, P = .005). There was an inverse association between duration of intervention and the magnitude of the association of exercise with depression (P = .002). No other characteristics were related to between-study heterogeneity. Pooled analysis of 5 trials with long-term follow-up (ie, that examined outcomes beyond the end of the intervention) suggested no long-term benefit (SMD, -0.01; 95% CI, -0.28 to 0.26), with no strong evidence of heterogeneity in this pooled analysis (I(2) = 23.4%, P = .27). There was no strong statistical evidence for small study bias (P > .27). Only 3 studies were assessed as high quality (adequately concealed random allocation, blinded outcome assessment, and intention-to-treat analysis). When we pooled results from these, the estimated beneficial effect of exercise was more modest (SMD, -0.19; 95% CI, -0.70 to 0.31) than the pooled result for all 13 studies, with no strong evidence of benefit.Our results suggest a short-term effect of exercise on depression: on average, depression scores 0.4 of a standard deviation lower in clinically depressed patients randomly assigned to an exercise intervention at the end of that intervention compared to those randomly assigned to a none exercise group. There is little evidence of a long-term beneficial effect of exercise in patients with clinical depression.

Timeline Follow-Back (TLFB) is a widely used, calendar-based measure of self-reported use of (among other things) illicit substances. We examined agreement between TLFB and biological measures for illicit substances. PubMed, PsycINFO, Cochrane CENTRAL, and EMBASE were searched in December 2010. 16,633 papers screened to identify those that measured illicit substance use by both TLFB and biological measures. We extracted data on agreement between TLFB and biological measures, sample size, study type, inclusion criteria of participants, and length of recall of TLFB. Twenty-nine papers were included, almost exclusively in substance-use-disorder populations. Some studies reported several overall agreement rates, e.g. over time. Lowest and highest weighted average agreement rates were: for cannabis, 87.3% (95% confidence interval 86.9% to 87.7%) and 90.9% (90.5% to 91.4%); for cocaine, 79.3% (79.1% to 79.6%) and 84.1% (83.9% to 84.2%); for opiates 94.0% (93.5% to 94.5%) for both weighted averages; and for studies not distinguishing between substances, 88.5% (88.4 to 88.7%) and 91.0% (90.7% to 91.2%). Higher agreement was found in populations without psychiatric comorbidity, and lower agreement in randomized controlled trials. Publication bias or selective outcome reporting bias was not detected. TLFB validly detects use of illicit substances in populations with substance use disorders. Using TLFB may limit the need for biological samples, making information on illicit substance use easier and less costly to obtain and analyze.

Over the last 15 years, a focus on early intervention in psychotic disorders has emerged. Initially, the early psychosis movement focused on timely recognition and phase-specific treatment of first-episode psychosis. However, early psychosis researchers suspected that pushing the point of intervention even further back to the prodromal phase of psychotic disorders may result in even better outcomes. This article reviews intervention research in the ultra-high-risk phase of psychotic disorders.A literature search of intervention trials with ultra-high-risk cohorts published after 1980 was conducted on PubMed with the search terms prodrome and intervention.All published intervention trials with ultra-high-risk cohorts.The first generation of intervention trials indicated that both pharmacologic and psychological intervention strategies may be of value in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder.Further controlled intervention trials with larger sample sizes are required in order to confirm and extend these findings. We argue that the clinical staging model provides a framework for the rationale and design of such studies, with simpler, safer, and more benign interventions being better candidates for first-line treatment, while more complex and potentially harmful treatments should be reserved for those cases in which response has failed to occur. Recent evidence indicates that neuroprotective agents, such as essential fatty acids, may be a suitable form of intervention for the ultra-high-risk phase of psychotic disorders, with a positive risk-benefit balance. Ethical aspects have become more salient given the recently observed declining transition rate in ultra-high-risk samples. We outline the key questions for the next generation of ultra-high-risk intervention trials.

Suicide is a major cause of death among patients with schizophrenia. Research indicates that at least 5–13% of schizophrenic patients die by suicide, and it is likely that the higher end of range is the most accurate estimate. There is almost total agreement that the schizophrenic patient who is more likely to commit suicide is young, male, white and never married, with good premorbid function, post-psychotic depression and a history of substance abuse and suicide attempts. Hopelessness, social isolation, hospitalization, deteriorating health after a high level of premorbid functioning, recent loss or rejection, limited external support, and family stress or instability are risk factors for suicide in patients with schizophrenia. Suicidal schizophrenics usually fear further mental deterioration, and they experience either excessive treatment dependence or loss of faith in treatment. Awareness of illness has been reported as a major issue among suicidal schizophrenic patients, yet some researchers argue that insight into the illness does not increase suicide risk. Protective factors play also an important role in assessing suicide risk and should also be carefully evaluated. The neurobiological perspective offers a new approach for understanding self-destructive behavior among patients with schizophrenia and may improve the accuracy of screening schizophrenics for suicide. Although, there is general consensus on the risk factors, accurate knowledge as well as early recognition of patients at risk is still lacking in everyday clinical practice. Better knowledge may help clinicians and caretakers to implement preventive measures. This review paper is the results of a joint effort between researchers in the field of suicide in schizophrenia. Each expert provided a brief essay on one specific aspect of the problem. This is the first attempt to present a consensus report as well as the development of a set of guidelines for reducing suicide risk among schizophenia patients.

No study has gathered evidence from all randomized clinical trials (RCTs) with anti-inflammatory drugs measuring antidepressant effects including a detailed assessment of side-effects and bias.We performed a systematic review identifying RCTs published prior to January 1, 2018, studying antidepressant treatment effects and side-effects of pharmacological anti-inflammatory intervention in adults with major depressive disorder (MDD) or depressive symptoms. Outcomes were depression scores after treatment, remission, response, and side-effects. Pooled standard mean differences (SMD) and risk ratios (RR) including 95% confidence intervals (95%-CI) were calculated.We identified 36 RCTs, whereof 13 investigated NSAIDs (N = 4214), 9 cytokine inhibitors (N = 3345), seven statins (N = 1576), 3 minocycline (N = 151), 2 pioglitazone (N = 77), and 2 glucocorticoids (N = 59). Anti-inflammatory agents improved depressive symptoms compared to placebo as add-on in patients with MDD (SMD = -0.64; 95%-CI = -0.88, -0.40; I2 = 51%; N = 597) and as monotherapy (SMD = -0.41; 95%-CI = -0.60, -0.22; I2 = 93%, N = 8825). Anti-inflammatory add-on improved response (RR = 1.76; 95%-CI = 1.44-2.16; I2 = 16%; N = 341) and remission (RR = 2.14; 95%-CI = 1.03-4.48; I2 = 57%; N = 270). We found a trend toward an increased risk for infections, and all studies showed high risk of bias.Anti-inflammatory agents improved antidepressant treatment effects. Future RCTs need to include longer follow-up, identify optimal doses and subgroups of patients that can benefit from anti-inflammatory intervention.

Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions.We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses.A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder.Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).

The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Excess mortality from diseases and medical conditions (natural death) in persons with psychiatric disorders has been extensively reported. Even in the Nordic countries with well-developed welfare systems, register based studies find evidence of an excess mortality. In recent years, cardiac mortality and death by diseases of the circulatory system has seen a decline in all the Nordic countries, but a recent paper indicates that women and men in Denmark, Finland, and Sweden, who had been hospitalised for a psychotic disorder, had a two to three-fold increased risk of dying from a cardiovascular disease. The aim of this study was to compare the mortality by diseases of the circulatory system among patients with bipolar disorder or schizophrenia in the three Nordic countries Denmark, Sweden, and Finland. Furthermore, the aim was to examine and compare life expectancy among these patients. Cause specific Standardized Mortality Rates (SMRs) were calculated for each specific subgroup of mortality. Life expectancy was calculated using Wiesler's method.The SMR for bipolar disorder for diseases of the circulatory system was approximately 2 in all countries and both sexes. SMR was slightly higher for people with schizophrenia for both genders and in all countries, except for men in Denmark. Overall life expectancy was much lower among persons with bipolar disorder or schizophrenia, with life expectancy being from 11 to 20 years shorter.Our data show that persons in the Nordic countries with schizophrenia or bipolar disorder have a substantially reduced life expectancy. An evaluation of the reasons for these increased mortality rates should be prioritized when planning healthcare in the coming years.

A promising treatment to prevent onset and improve outcomes in patients at ultrahigh risk for psychosis is dietary supplementation with long-chain ω-3 polyunsaturated fatty acids (PUFAs).To determine whether treatment with ω-3 PUFAs in combination with a high-quality psychosocial intervention (cognitive behavioral case management [CBCM]) is more effective than placebo plus CBCM.NEURAPRO, a double-blind, placebo-controlled, randomized clinical trial, was conducted from March 1, 2010, to September 30, 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. The primary analysis used the intention-to-treat approach.A daily dose of 1.4 g of ω-3 PUFAs or placebo (paraffin oil), plus 20 or fewer sessions of CBCM over the 6-month study period.The primary outcome was transition to psychosis status at 6 months. The secondary outcomes were general levels of psychopathology and functioning, as assessed by the Brief Psychiatric Rating Scale (BPRS) (range, 24-168), Scale for the Assessment of Negative Symptoms (SANS) (range, 0-125), Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60), Young Mania Rating Scale (YMRS) (range, 0-44), Social and Occupational Functioning Assessment Scale (SOFAS) (range, 0-100), and the Global Functioning: Social and Role scale (range, 0-10). For SOFAS and Global Functioning: Social and Role scale, higher scores were better; for other measures, lower scores were better.In this study of 304 adults at ultrahigh risk for psychotic disorders, 153 (50.3%) received ω-3 PUFAs and 151 (49.7%) received placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The Kaplan-Meier-estimated 6-month transition rates were 5.1% (95% CI, 1.3%-8.7%) in the control group and 6.7% (95% CI, 2.3%-10.8%) in the ω-3 PUFA group. At 12 months, the rates were 11.2% (95% CI, 5.5%-16.7%) in the control group and 11.5% (95% CI, 5.8%-16.9%) in the ω-3 PUFA group. No significant difference was observed between the transition rates of both groups (hazard ratio, 1.1; 95% CI, 0.55-2.23; P = .76, stratified log-rank test).This trial clearly failed to replicate the findings of the original single-center trial. The most likely explanation is that ω-3 PUFAs lack efficacy under these conditions. However, the lower-than-expected transition rate may have prevented a test of the main hypothesis. Given the substantial symptomatic and functional improvement in both groups, the other treatments received (ie, CBCM and antidepressants) likely produced a ceiling effect beyond which ω-3 PUFAs, even if effective, could not be shown to confer additional benefits. Nevertheless, the main conclusion is that ω-3 PUFAs are not effective under conditions where good quality, evidence-based psychosocial treatment is available.anzctr.org.au Identifier: 12608000475347.

Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).

More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Summary Patients who recover from an acute episode of psychosis are frequently prescribed prophylactic antipsychotics for many years, especially if they are diagnosed as having schizophrenia. However, there is a dearth of evidence concerning the long-term effectiveness of this practice, and growing concern over the cumulative effects of antipsychotics on physical health and brain structure. Although controversy remains concerning some of the data, the wise psychiatrist should regularly review the benefit to each patient of continuing prophylactic antipsychotics against the risk of side-effects and loss of effectiveness through the development of supersensitivity of the dopamine D 2 receptor. Psychiatrists should work with their patients to slowly reduce the antipsychotic to the lowest dose that prevents the return of distressing symptoms. Up to 40% of those whose psychosis remits after a first episode should be able to achieve a good outcome in the long term either with no antipsychotic medication or with a very low dose.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942–2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.71; 95% CI 0.33–1.09) and affective disorders (4 studies [298 patients]; SMD = 0.41; 95% CI 0.23–0.60, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.41; 95% CI 0.15–0.67, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.80; 95% CI 0.39–1.21, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.68; 95% CI 0.30–1.06), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = −0.62; 95% CI −1.13 to −0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.55; 95% CI 0.35–0.76; I2 = 1%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17–0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2–6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

Objective: The authors investigated the rates of conversion to schizophrenia and bipolar disorder after a substance-induced psychosis, as well as risk factors for conversion. Method: All patient information was extracted from the Danish Civil Registration System and the Psychiatric Central Research Register. The study population included all persons who received a diagnosis of substance-induced psychosis between 1994 and 2014 (N=6,788); patients were followed until first occurrence of schizophrenia or bipolar disorder or until death, emigration, or August 2014. The Kaplan-Meier method was used to obtain cumulative probabilities for the conversion from a substance-induced psychosis to schizophrenia or bipolar disorder. Cox proportional hazards regression models were used to calculate hazard ratios for all covariates. Results: Overall, 32.2% (95% CI=29.7–34.9) of patients with a substance-induced psychosis converted to either bipolar or schizophrenia-spectrum disorders. The highest conversion rate was found for cannabis-induced psychosis, with 47.4% (95% CI=42.7–52.3) converting to either schizophrenia or bipolar disorder. Young age was associated with a higher risk of converting to schizophrenia. Self-harm after a substance-induced psychosis was significantly linked to a higher risk of converting to both schizophrenia and bipolar disorder. Half the cases of conversion to schizophrenia occurred within 3.1 years after a substance-induced psychosis, and half the cases of conversion to bipolar disorder occurred within 4.4 years. Conclusions: Substance-induced psychosis is strongly associated with the development of severe mental illness, and a long follow-up period is needed to identify the majority of cases.

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls).Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15).Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

<h3>Importance</h3> Anxiety and stress-related disorders are among the most common mental disorders. Although family and twin studies indicate that both genetic and environmental factors play an important role underlying their etiology, the genetic underpinnings of anxiety and stress-related disorders are poorly understood. <h3>Objectives</h3> To estimate the single-nucleotide polymorphism–based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the association of psychiatric comorbidities with genetic findings. <h3>Design, Setting, Participants</h3> This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. <h3>Main Outcomes and Measures</h3> Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. <h3>Results</h3> The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) between 2001-2005. Standard association analysis revealed variants in<i>PDE4B</i>to be associated with anxiety and stress-related disorder (rs7528604;<i>P</i> = 5.39 × 10⁻¹¹; odds ratio = 0.89; 95% CI, 0.86-0.92). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of<i>PDE4B</i>variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in<i>Pde4b</i>expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (<i>P</i> = .002;<i>t</i> = −3.33) and the hippocampus (<i>P</i> = .001;<i>t</i> = −3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success. <h3>Conclusions and Relevance</h3> This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes. Furthermore, we highlight the candidate gene<i>PDE4B</i>as a robust risk locus pointing to the potential of<i>PDE4B</i>inhibitors in treatment of these disorders.

Abstract Background During the last decades, a renewed interest for negative symptoms (NS) was brought about by the increased awareness that they interfere severely with real-life functioning, particularly when they are primary and persistent. Methods In this guidance paper, we provide a systematic review of the evidence and elaborate several recommendations for the conceptualization and assessment of NS in clinical trials and practice. Results Expert consensus and systematic reviews have provided guidance for the optimal assessment of primary and persistent negative symptoms; second-generation rating scales, which provide a better assessment of the experiential domains, are available; however, NS are still poorly assessed both in research and clinical settings. This European Psychiatric Association (EPA) guidance recommends the use of persistent negative symptoms (PNS) construct in the context of clinical trials and highlights the need for further efforts to make the definition of PNS consistent across studies in order to exclude as much as possible secondary negative symptoms. We also encourage clinicians to use second-generation scales, at least to complement first-generation ones. The EPA guidance further recommends the evidence-based exclusion of several items included in first-generation scales from any NS summary or factor score to improve NS measurement in research and clinical settings. Self-rated instruments are suggested to further complement observer-rated scales in NS assessment. Several recommendations are provided for the identification of secondary negative symptoms in clinical settings. Conclusions The dissemination of this guidance paper may promote the development of national guidelines on negative symptom assessment and ultimately improve the care of people with schizophrenia.

Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally.We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation.We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries' COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries' income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well.Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue.None.

<h3>Importance</h3> There is limited evidence supporting an association of autism spectrum disorder (ASD) with suicidality and the risk factors for suicide attempt and suicide among people with ASD. Existing research highlights the need for national cohort studies. <h3>Objectives</h3> To analyze whether people with ASD have higher rates of suicide attempt and suicide compared with people without ASD using national register data, identify potential risk factors for suicide attempt and suicide among those with ASD, and examine associations with comorbid disorders. <h3>Design, Setting, and Participants</h3> In this cohort study, nationwide register data from January 1, 1995, to December 31, 2016, were gathered on 6 559 266 individuals in Denmark aged 10 years or older. Statistical analysis was performed from November 20, 2018, to November 21, 2020. <h3>Main Outcomes and Measures</h3> Rates of suicide attempt and suicide among persons with ASD were compared with rates among persons without ASD, using Poisson regression models to calculate incidence rate ratios adjusted for sex, age, and time period. <h3>Results</h3> Of the total study population of 6 559 266 individuals, 35 020 individuals (25 718 male [73.4%]; mean [SD] age at diagnosis, 13.4 [9.3] years) received a diagnosis of ASD. A total of 64 109 incidents of suicide attempts (587 [0.9%] among individuals with ASD) and 14 197 suicides (53 [0.4%] among individuals with ASD) were recorded. Persons with ASD had a more than 3-fold higher rate of suicide attempt (adjusted incidence rate ratio [aIRR], 3.19; 95% CI, 2.93-3.46) and suicide (aIRR, 3.75; 95% CI, 2.85-4.92) than those without ASD. For individuals with ASD, the aIRR for suicide attempt among female individuals was 4.41-fold (95% CI, 3.74-5.19) higher compared with male individuals; for individuals without ASD, the aIRR for female individuals was 1.41-fold (95% CI, 1.39-1.43) higher compared with male individuals. Higher rates of suicide attempt were noted across all age groups for those with ASD. Persons with a diagnosis of ASD only had an aIRR of 1.33 (95% CI, 0.99-1.78) for suicide attempt, whereas those with other comorbid disorders had an aIRR of 9.27 (95% CI, 8.51-10.10) for suicide attempt compared with those without any psychiatric disorders. A total of 542 of 587 individuals with ASD (92.3%) who attempted suicide had at least 1 other comorbid condition and 48 of 53 individuals with ASD (90.6%) who died by suicide had at least 1 other comorbid condition. <h3>Conclusions and Relevance</h3> This nationwide retrospective cohort study found a higher rate of suicide attempt and suicide among persons with ASD. Psychiatric comorbidity was found to be a major risk factor, with more than 90% of those with ASD who attempted or died by suicide having another comorbid condition. Several risk factors are different from the risk factors in the general population, which suggests the need for tailored suicide prevention strategies.

Negative symptoms of schizophrenia remain a major therapeutic challenge. The progress in the conceptualization and assessment is not yet fully reflected by treatment research. Nevertheless, there is a growing evidence base regarding the effects of biological and psychosocial interventions on negative symptoms. The importance of the distinction between primary and secondary negative symptoms for treatment selection might seem evident, but the currently available evidence remains limited. Good clinical practice is recommended for the treatment of secondary negative symptoms. Antipsychotic treatment should be optimized to avoid secondary negative symptoms due to side effects and due to positive symptoms. For most available interventions, further evidence is needed to formulate sound recommendations for primary, persistent, or predominant negative symptoms.However, based on currently available evidence recommendations for the treatment of undifferentiated negative symptoms (including both primary and secondary negative symptoms) are provided. Although it has proven difficult to formulate an evidence-based recommendation for the choice of an antipsychotic, a switch to a second-generation antipsychotic should be considered for patients who are treated with a first-generation antipsychotic. Antidepressant add-on to antipsychotic treatment is an option. Social skills training is recommended as well as cognitive remediation for patients who also show cognitive impairment. Exercise interventions also have shown promise. Finally, access to treatment and to psychosocial rehabilitation should be ensured for patients with negative symptoms. Overall, there is definitive progress in the field, but further research is clearly needed to develop specific treatments for negative symptoms.

Although cognitive impairment is a core symptom of schizophrenia related to poorer outcomes in different functional domains, it still remains a major therapeutic challenge. To date, no comprehensive treatment guidelines for cognitive impairment in schizophrenia are implemented.The aim of the present guidance paper is to provide a comprehensive meta-review of the current available evidence-based treatments for cognitive impairment in schizophrenia. The guidance is structured into three sections: pharmacological treatment, psychosocial interventions, and somatic treatments.Based on the reviewed evidence, this European Psychiatric Association guidance recommends an appropriate pharmacological management as a fundamental starting point in the treatment of cognitive impairment in schizophrenia. In particular, second-generation antipsychotics are recommended for their favorable cognitive profile compared to first-generation antipsychotics, although no clear superiority of a single second-generation antipsychotic has currently been found. Anticholinergic and benzodiazepine burdens should be kept to a minimum, considering the negative impact on cognitive functioning. Among psychosocial interventions, cognitive remediation and physical exercise are recommended for the treatment of cognitive impairment in schizophrenia. Noninvasive brain stimulation techniques could be taken into account as add-on therapy.Overall, there is definitive progress in the field, but further research is needed to develop specific treatments for cognitive impairment in schizophrenia. The dissemination of this guidance paper may promote the development of shared guidelines concerning the treatment of cognitive functions in schizophrenia, with the purpose to improve the quality of care and to achieve recovery in this population.

Abstract Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Importance The OPUS 20-year follow-up is the longest follow-up of a randomized clinical trial testing early intervention services (EIS) among individuals with first-episode schizophrenia spectrum disorder. Objective To report on long-term associations of EIS compared with treatment as usual (TAU) for first-episode schizophrenia spectrum disorder. Design, Setting, and Participants A total of 547 individuals were included in this Danish multicenter randomized clinical trial between January 1998 and December 2000 and allocated to early intervention program group (OPUS) or TAU. Raters who were blinded to the original treatment performed the 20-year follow-up. A population-based sample aged 18 to 45 years with first-episode schizophrenia spectrum disorder were included. Individuals were excluded if they were treated with antipsychotics (&amp;amp;gt;12 weeks prior to randomization), had substance-induced psychosis, had mental disability, or had organic mental disorders. Analysis took place between December 2021 and August 2022. Interventions EIS (OPUS) consisted of 2 years of assertive community treatment including social skill training, psychoeducation, and family involvement by a multidisciplinary team. TAU consisted of the available community mental health treatment. Main Outcomes and Measures Psychopathological and functional outcomes, mortality, days of psychiatric hospitalizations, number of psychiatric outpatient contacts, use of supported housing/homeless shelters, symptom remission, and clinical recovery. Results Of 547 participants, 164 (30%) were interviewed at 20-year follow-up (mean [SD] age, 45.9 [5.6] years; 85 [51.8%] female). No significant differences were found between the OPUS group compared with the TAU group on global functional levels (estimated mean difference, −3.72 [95% CI, −7.67 to 0.22]; P = .06), psychotic symptom dimensions (estimated mean difference, 0.14 [95% CI, −0.25 to 0.52]; P = .48), and negative symptom dimensions (estimated mean difference, 0.13 [95% CI, −0.18 to 0.44]; P = .41). The mortality rate was 13.1% (n = 36) in the OPUS group and 15.1% (n = 41) in the TAU group. Likewise, no differences were found 10 to 20 years after randomization between the OPUS and TAU groups on days of psychiatric hospitalizations (incidence rate ratio, 1.20 [95% CI, 0.73-1.20]; P = .46) or number of outpatient contacts (incidence rate ratio, 1.20 [95% CI, 0.89-1.61]; P = .24). Of the entire sample, 53 participants (40%) were in symptom remission and 23 (18%) were in clinical recovery. Conclusions and Relevance In this follow-up study of a randomized clinical trial, no differences between 2 years of EIS vs TAU among individuals with diagnosed schizophrenia spectrum disorders at 20 years were found. New initiatives are needed to maintain the positive outcomes achieved after 2 years of EIS and furthermore improve very long-term outcomes. While registry data was without attrition, interpretation of clinical assessments are limited by high attrition rate. However, this attrition bias most likely confirms the lack of an observed long-term association of OPUS with outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT00157313

Importance The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)–derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal ( z &amp;amp;lt; −1.96) or supranormal ( z &amp;amp;gt; 1.96) scores. Results Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [&amp;amp;lt;11.42%]) and similar to that of healthy individuals (&amp;amp;lt;115 individuals [&amp;amp;lt;9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = −0.08; 95% CI, −0.13 to −0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

OBJECTIVES. This study investigated the influence of psychosocial stress, maternal schooling, social support, psychological well-being, alcohol, and smoking on intrauterine growth retardation and premature delivery. METHODS. At a Copenhagen university hospital, 2432 pregnant women completed a questionnaire on general health, psychosocial stressors, and sociodemographic characteristics. RESULTS. In 212 cases (8.7%) the women delivered prematurely. Preterm delivery as associated with psychosocial stress (adjusted odds ratio [OR]=1.14 for each 1-point increase on the psychosocial stressor 5-point scale and 1.92 for the whole scale) and poor school education (adjusted OR=2.62 for 7-9 years of schooling, 1.91 for 10 years, and 1.0 for 11-13 years). In 152 cases (6.3%), infants had a birthweight below the 10th percentile. Intrauterine growth retardation was associated with smoking, daily drinking, school education, and social network variables. In a multiple logistic regression model, intrauterine growth retardation was associated with smoking habits (adjusted OR=2.40 for 0-9 cigarettes daily, 2.68 for 10-15 daily, and 2.88 for more than 15 daily). CONCLUSIONS. Psychosocial stressors and limited duration of schooling appeared to influence preterm delivery. Smoking habits influenced intrauterine growth retardation.

In a population-based study, 3021 women in a central Copenhagen district received a questionnaire on environmental and psychological factors during mid-gestation. Of these, 70 women were selected consecutively on the basis of moderate to severe stressful life-events (DSM-III-R categories 3 to 5), in combination with an inadequate social network. They were compared with 50 non-stressed women with an intact social network. Stress and smoking significantly affected birthweight and head circumference. When birthweight was corrected, stress remained a significant determinant of small head circumference, indicating a specific effect on brain development. Stress also led to a suboptimal Prechtl neonatal neurological score. These findings suggest the existence of a fetal stress syndrome with adverse effects on fetal development, including deficient brain development.

To explore the risk of suicide associated with occupation while evaluating the impact of socio-economic, demographic and psychiatric differences.A nested case-control study with 3195 suicides and 63 900 matched controls. Information on causes of death, occupation, psychiatric admission, marital status and socio-economic factors was obtained from routine registers.Across the 55 occupations investigated, the risk of suicide ranged from 2.73 [95% confidence interval (CI) 1.77-4.22] among doctors to 0.44 (95% CI 0.27-0.72) among architects and engineers compared with primary school teachers. With the exception of doctors and nurses, most of the excess risk of suicide associated with particular occupations is explained by the social and economic characteristics of people in those occupations. Much, but not all, of the excess risk in doctors and nurses is due to their increased use of self-poisoning, a method for which they have the knowledge to use effectively. Occupation has little association with suicide among people who suffer from a psychiatric illness, except for doctors, where the excess risk is 3.62 (p=0.007).Most of the considerable variation in suicide risk across occupations is explained by socio-economic factors, except for doctors and nurses. Apart from in doctors, the risk of suicide has little association with occupation among people who suffer from a psychiatric illness. Restriction of access to lethal means is an important strategy in suicide prevention.

Background The increased mortality of homeless people compared with non-homeless people might be linked to psychiatric disorders. However, homeless people are, because of their insufficient accommodation, difficult to sample and monitor, which has limited previous studies. We aimed to assess registered psychiatric disorders, mortality, and predictors of mortality in the homeless shelter population in Denmark. Methods We did a nationwide, prospective, register-based cohort study of homeless people aged 16 years and older who were registered in the Danish Homeless Register between Jan 1, 1999, and Dec 31, 2009. We calculated the proportion of registered psychiatric disorders, overall and cause-specific standardised mortality ratio (SMR), and life expectancy. Hazard ratios (HRs) were used to assess predictors of death. Findings 32 711 homeless people (23 040 men and 9671 women) were included in the study population. 14 381 men (62·4%) and 5632 women (58·2%) had registered psychiatric disorders, and 11 286 men (49·0%) and 3564 women (36·9%) had a substance abuse diagnosis. During the study period, 3839 men (16·7%) and 951 women (9·8%) died. The overall SMR for men was 5·6 (95% CI 5·4–5·8) and for women was 6·7 (6·2–7·1), and external causes accounted for 1161 (27·9%) of 4161 deaths for which information on the cause was available. Remaining life expectancy at age 15–24 years was 21·6 years (95% CI 21·2–22·1) and 17·4 years (16·4–18·5) lower for homeless men and women, respectively, than the general population. Registered substance abuse disorder was associated with the highest mortality risk compared with no psychiatric contact registered (adjusted HR 1·4, 95% CI 1·3–1·5 for men; 1·7, 1·4–2·1 for women). Interpretation Health problems are extensive in the homeless shelter population and there is an urgent need for more sustained efforts to reduce the high morbidity and mortality, especially from external causes. Register data is an important resource to supplement existing knowledge on homeless people with more valid and detailed information. Funding The Danish Council for Independent Research.

Those with first-episode psychosis are at high-risk of suicide.To identify predictive factors for suicidal thoughts, plans and attempts, and to investigate the rate of suicides and other deaths during the 5 years after first diagnosis and initiation of treatment.A longitudinal, prospective, 5-year follow-up study of 547 individuals with first-episode schizophrenia spectrum psychosis. Individuals presenting for their first treatment in mental health services in two circumscribed urban areas in Denmark were included in a randomised controlled trial of integrated v. standard treatment. All participants were followed in the Danish Cause of Death Register for 5 years. Suicidal behaviour and clinical and social status were assessed using validated interviews and rating scales at entry, and at 1- and 2-year follow-ups.Sixteen participants died during the follow-up. We found a strong association between suicidal thoughts, plans and previous attempts, depressive and psychotic symptoms and young age, and with suicidal plans and attempts at 1- and 2-year follow-up.In this first-episode cohort depressive and psychotic symptoms, especially hallucinations, predicted suicidal plans and attempts, and persistent suicidal behaviour and ideation were associated with high risk of attempted suicide.

Only a few randomized clinical trials have tested the effect on transition rates of intervention programs for patients with sub-threshold psychosis-like symptoms.To examine whether integrated treatment reduced transition to psychosis for first-contact patients diagnosed with schizotypal disorder.Seventy-nine patients were randomized to integrated treatment or standard treatment. Survival analysis with multivariate Cox-regression was used to identify factors determinant for transition to psychotic disorder.In the multivariate model, male gender increased risk for transition to psychotic disorder (relative risk=4.47, (confidence interval 1.30-15.33)), while integrated treatment reduced the risk (relative risk=0.36 (confidence interval 0.16-0.85)). At two-year follow-up, the proportion diagnosed with a psychotic disorder was 25.0% for patients randomized to integrated treatment compared to 48.3% for patients randomized to standard treatment.Integrated treatment postponed or inhibited onset of psychosis in significantly more cases than standard treatment.

Previous research has found an increased risk of schizophrenia in individuals with autoimmune diseases and smaller but significant associations with a family history of autoimmune diseases. This study investigates, for the first time, the association between schizophrenia and subsequent autoimmune diseases (the reverse temporality) and also considers the effect of infections, a possible risk factor for both schizophrenia and autoimmune diseases.Danish nationwide registers were linked to establish a cohort of 3.83 million people, identifying 39,364 individuals with schizophrenia-like psychosis and 142,328 individuals with autoimmune disease. Data were analyzed using survival analysis and adjusted for calendar year, age, and sex.Individuals with schizophrenia had an elevated risk of subsequent autoimmune diseases, with an incidence rate ratio of 1.53 (95% CI=1.46-1.62). Among persons without hospital contacts for infections, the effect of having schizophrenia was smaller, with an increased incidence rate ratio of 1.32 (95% CI=1.22-1.43) for autoimmune diseases. For individuals with schizophrenia as well as hospital contacts for infections, the combined risk of autoimmune diseases was 2.70 (95% CI=2.51-2.89). A family history of schizophrenia slightly increased the overall risk of developing autoimmune diseases (incidence rate ratio=1.06, 95% CI=1.02-1.09). Autoimmune diseases developed subsequently in 3.6% of people with schizophrenia, and 3.1% of people with autoimmune diseases had a family history of schizophrenia.The increased risk of subsequent autoimmune diseases in individuals with schizophrenia may involve neuropsychiatric manifestations from the undiagnosed autoimmune disease, medical treatment or lifestyle associated with schizophrenia, or common etiological mechanisms, such as infections and shared genetic factors.

This paper aims to investigate the predictors of good outcome after first-episode non-affective psychosis and the clinical and social trajectories of those that recover. A cohort of 255 patients with first-episode non-affective psychosis was interviewed 5 years after first diagnosis and treatment. Recovery was defined as working or studying, having a GAF-function score of 60 or above, having remission of negative and psychotic symptoms, and not living in a supported housing facility or being hospitalized during the last 2 years before the five-year follow-up interview. A total of 40 (15.7%) were found to be recovered, and 76 (29.8%) had a job or were studying after 5 years. Of those working, as many as 20 still had psychotic symptoms. Also notable is that out of the 40 recovered, less than half were recovered after 2 years. Recovery after 5 years was predicted by female sex (OR 2.4, 95% CI 1.0–5.8), higher age (OR 0.91, 95% CI 0.83–0.99), pre-morbid social adaptation (OR 0.72, 95% CI 0.56–0.93), growing up with both parents (OR 2.6, 95% CI 1.0–6.8) and low level of negative symptoms (OR 0.51, 95% CI 0.33 to 0.77) at baseline. Our findings suggest that a stable social life with normal social functioning has a predictive value for good outcome. These measures might be influenced by negative symptoms, but in the multivariate analysis with negative symptoms included they have an independent effect. Also our findings suggest that, after first-episode psychosis, some patients can still experience psychotic symptoms, but have a job and a fairly stable life.

Recovery, the optimal goal in treatment, is the attainment of both symptomatic and functional remission over a sustained period of time. Identification of factors that promote recovery can help develop interventions that facilitate good outcomes for people with first episode psychosis. To examine long-term outcomes within a cohort of people with first episode psychosis in relation to symptom remission, functioning and recovery, 10 years after diagnosis. The study had a prospective design. Participants from the OPUS trial (1998–2000) (n = 496) completed a series of interviews and questionnaires to measure current levels of psychopathology and social/vocational functioning, ten years after diagnosis. Predictors of recovery were identified using socio-demographic and clinical characteristics collected at baseline. A total of 304 participants were interviewed, giving a follow-up rate of 61%. A total of 42 people (14%) met the criteria for symptomatic and psychosocial recovery at 10 years. A multivariable binary logistic regression analysis indicated that baseline predictors accounted for 22% of the variance of full recovery. Lower severity of negative symptoms at baseline (Odds Ratio (OR) 0.53, 95% confidence interval CI 0.36–0.78, p < 0.001) and earlier age of diagnosis (OR 0.92, 95% CI 0.86–0.99, p < 0.05) predicted better rates of recovery at 10 years. Results of this study indicated that negative symptoms could play a central role in the process of recovery from schizophrenia. A challenge for clinicians and researchers is to understand the mechanisms behind negative symptoms and develop interventions that can prevent or ameliorate these symptoms in order to promote recovery.

Knowledge about course of illness can help clinicians to develop effective interventions and improve treatment outcomes. The goal of this study was to construct positive and negative symptom trajectories based on structured clinical assessments collected over 10years within a cohort of people with first episode psychosis.A cohort of 496 people with first episode psychosis (ICD-10, F20-28) originally recruited for the OPUS study (1998-2000) and treated in community psychiatric services were rated on clinical symptoms at 5 different occasions across ten years. Psychopathology was assessed using the Scales for Assessment of Positive and Negative Symptoms. Symptom trajectories were constructed using Latent Class Analysis.Five distinct trajectories were identified for positive symptoms (response - 47%, delayed response - 12%, relapse - 15%, non-response - 13% and episodic response - 13%). Four distinct trajectories were identified for negative symptoms (response - 28%, delayed response - 19%, relapse - 26% and non-response - 27%). Multivariable regression analysis of baseline characteristics identified that longer duration of untreated psychosis (OR 1.27-1.47, p<0.05) and substance abuse (OR 3.47-5.90, p<0.01) were associated with poorer positive symptom trajectories (higher levels of psychotic symptoms) while poor social functioning (OR 1.34-5.55, p<0.05), disorganized symptoms (OR 2.01-2.38, p<0.05) and schizophrenia diagnosis (OR 5.70-8.86, p<0.05) were associated with poorer negative symptom trajectories (higher levels of negative symptoms). A proportion of people displayed significant changes in symptoms several years after diagnosis.Trajectories of illness for positive and negative symptoms were heterogeneous among people with first episode psychosis. Positive symptoms showed a general pattern of reduction and stabilization over time while negative symptoms typically showed less variation over the ten years. Results have implications for the focus, timing and length of interventions in first episode psychosis.

The purpose of this study was to assess the association between IL-6 and CRP with depressive items and cognitive function. We included 112 outpatients with major depression from an exercise trial and 57 healthy controls. IL-6, high sensitive CRP (hsCRP), and cognitive function were assessed in all subjects. After baseline assessment, patients were randomised to either a 3months exercise intervention or an exercise control group. Post-intervention IL-6, hsCRP, depressive symptoms, and cognitive function were reassessed in the patient group. IL-6 and hsCRP were significantly increased in depressed patients compared to healthy controls (p=0.02 and 0.04). These differences were no longer significant after adjustment for lifestyle associated variables. We found no association between immune markers and specific depressive symptoms at baseline or as change over time. Regarding the cognitive tests, IL-6 was positively associated with Serial sevens (p=0.008) and hsCRP was inversely associated with Trail making A (p=0.02) and design fluency (p=0.001) at baseline. At 3months follow-up IL-6 and hsCRP levels did not significantly change from baseline and did not differ between the two patient groups. Depression scores was lower compared to baseline but did not differ between groups. Combining the two groups, a decrease in IL-6 was associated to decreased verbal fluency (p=0.02), and a decrease in hsCRP was associated with improvement in Trail making A (p=0.005). In conclusion, the level of IL-6 and hsCRP was increased in depressed outpatients but was not associated to specific depressive symptoms. In terms of cognitive function, we found that higher hsCRP levels were associated to lower psychomotor speed both at baseline and at follow-up.

Many studies have confirmed that the risk of suicide in patients with first-episode psychosis (FEP) is high, and high rates of premature mortality, particularly from suicide, may occur in the early phases of schizophrenia. However, suicide rates are difficult to measure in FEP patients, even in carefully defined samples, and there is relatively little specific information about the risk of suicide at illness onset or retrospectively concerning the untreated psychotic period. This selected review of the literature investigates suicidal behaviour with particular regard to severe suicidality (plans and attempts) and risk factors associated with suicide in FEP patients. A search was performed to identify all papers and book chapters during the period 1965-2010, and approximately 100 studies met the inclusion criteria. Most of evidence suggests that risk of suicidal behaviour is relatively high in FEP patients. The research reports highlight the need for universal, comprehensive, public mental health interventions aimed, not only toward early detection, but also toward the rapid engagement in treatment of people with psychoses. These interventions should include an adequate assessment of suicidal behaviour in patients with FEP, and an examination of the efficacy of specific components of the interventions.

A head injury, especially a severe head injury or one occurring between the ages of 11 and 15, increased the risk for subsequent schizophrenia by 65%, the risk of depression by 59%, the risk of bipolar disorder by 28%, and the risk of organic mental disorders by more than 400% in this largest-to-date analysis of data from over 100,000 individuals.

Specialized early intervention programs such as The Danish OPUS treatment are efficient in treating patients with a first episode of psychosis (FEP) at least after 2 and 5 years. Few studies have examined long-term outcomes of these interventions.To examine the effect of 2 years of OPUS vs treatment as usual (TAU) within an FEP cohort, 10 years after inclusion into the OPUS trial.From 1998 to 2000, participants were randomized to OPUS or TAU. Ten years later, we conducted comprehensive interviews and performed register-based follow-up on all participants in national Danish registers. We analyzed participants according to the intention-to-treat principle.Of the 547 participants included in the study, 347 (63.4%) took part in this follow-up. While there was evidence of a differential 10-year course in the development of negative symptoms, psychiatric bed days, and possibly psychotic symptoms in favor of OPUS treatment, differences were driven by effects at earlier follow-ups and had diminished over time. Statistically significant differences in the course of use of supported housing were present even after 8-10 years. There were no differences between OPUS and TAU regarding income, work-related outcomes, or marital status.Most of the positive short-term effects of the OPUS intervention had diminished or vanished at this long-term follow-up. We observed a clear tendency that OPUS treatment leads to fewer days in supported housing. There is a need for further studies investigating if extending the intervention will improve outcomes more markedly at long-term follow-ups.

Family studies have shown an aggregation of suicidal behavior in families. Yet, molecular studies are needed to identify loci accounting for genetic heritability. We conducted a genome-wide association study and estimated single nucleotide polymorphisms (SNP) heritability for a suicide attempt. In a case-cohort study, national data on all individuals born in Denmark after 1981 and diagnosed with severe mental disorders prior to 2013 (n = 57,377) and individuals from the general population (n = 30,000) were obtained. After quality control, the sample consisted of 6024 cases with an incidence of suicide attempt and 44,240 controls with no record of a suicide attempt. Suggestive associations between SNPs, rs6880062 (p-value: 5.4 × 10−8) and rs6880461 (p-value: 9.5 × 10−8), and suicide attempt were identified when adjusting for socio-demographics. Adjusting for mental disorders, three significant associations, all on chromosome 20, were identified: rs4809706 (p-value: 2.8 × 10−8), rs4810824 (p-value: 3.5 × 10−8), and rs6019297 (p-value: 4.7 × 108). Sub-group analysis of cases with affective disorders revealed SNPs associated with suicide attempts when compared to the general population for gene PDE4B. All SNPs explained 4.6% [CI-95: 2.9–6.3%] of the variation in suicide attempt. Controlling for mental disorders reduced the heritability to 1.9% [CI-95: 0.3–3.5%]. Affective and autism spectrum disorders exhibited a SNP heritability of 5.6% [CI-95: 1.9–9.3%] and 9.6% [CI-95: 1.1–18.1%], respectively. Using the largest sample to date, we identified significant SNP associations with suicide attempts and support for a genetic transmission of suicide attempt, which might not solely be explained by mental disorders.

The suicide rates in Denmark have been declining during the last two decades. The decline was relatively larger among women than among men. All age groups experienced a decline except the very young with stable rates and the very old with increasing rates. The Universal, Selective, Indicated (USI) model recommended by Institute of Medicine was used as a framework for the thesis. Universal preventive interventions are directed toward the entire population; selective interventions are directed toward individuals who are at greater risk for suicidal behaviour; and indicated preventions are targeted at individuals who have already begun self-destructive behaviour. At the universal level, a review was carried out to highlight the association between availability of methods for suicide and suicide rate. There were mostly studies of firearms, and the conclusion of the review was that there was clear indication of restricted access to lethal means was associated with decline in suicide with that specific method, and in many cases also with overall suicide mortality. Restricting access is especially important for methods with high case fatality rate. Our own study indicated a beneficial effect on suicide rates of restrictions in access to barbiturates, dextropropoxyphen, domestic gas and car exhaust with high content of carbon monoxide. Although a range of other factors in the society might also be of importance, it was concluded that restrictions in access to dangerous means for suicide were likely to play an important role in reducing suicide rates in Denmark, especially for women. At the selective level, there are several important risk groups such as psychiatric patients, persons with alcohol and drug abuse, persons with newly diagnosed severe physical illness, all who previously attempted suicide, and groups of homeless, institutionalized, prisoners and other socially excluded persons. The thesis focused on homeless persons and psychiatric patients, especially patients with schizophrenia and related disorders. The thesis contains a review of the risk of suicide in homeless. In all the studies included, increased suicide mortality was found, and in the studies that evaluated suicide risk in different age groups, the excess suicide mortality was most dominant in younger age groups. Our own study revealed an increased risk of suicide, and in univariate analysis, significant predictors for suicide were found to be associated with shortest stay in hostel less than 11 days and more than one stay during one year. The thesis also contains a review of the risk of suicide in first-episode patients with schizophrenia, and it was concluded on the basis of the identified studies that long-term risk of suicide was not 10 percent as previously accepted, but lower. Risk factors for suicide among patients with schizophrenia were evaluated in case control studies, in nested case control studies, and in prospective studies. The following risk factors were the most important and frequently observed predictors: male gender, young age, short duration of illness, many admissions during last year, current inpatient, short time since discharge, previous and recent suicide attempt, co-morbid depression, drug abuse, poor compliance with medication, poor adherence to treatment, high IQ, and suicidal ideations. The results of analyses of psychotic symptoms as risk factor for suicide were contradictory, but a recent meta-analysis concluded that both hallucinations and delusions seemed to be protective; however, there was a non-significant tendency that command hallucinations were associated with higher suicide risk. Prevention of suicide in schizophrenia must especially focus on improving assessment of risk of suicide during inpatient treatment and the first week after discharge, and special attention must be paid to patients with one or more of the identified risk factors. There is a need for large randomised clinical trials evaluating the effect on suicide and suicide attempt of psychosocial and pharmacological treatment in schizophrenia. In our own study, we did not find any effect of integrated treatment on attempted suicide, but there was an effect on hopelessness and a trend toward lower prevalence of depression among patients in the integrated treatment. There were four suicides and one probable suicide (drowning) in standard treatment and one suicide in integrated treatment at two-year follow-up, but the study did not have sufficient power to detect these differences in proportion to who committed suicide; more than one thousand patients should have been in each treatment condition in order for these differences in proportion to be significant. At the indicated prevention level, a literature review was carried out regarding risk of suicide attempt and suicide in short-term, medium-term and long-term follow-up of persons who attempted suicide. It was concluded that the risk of repetition in short- and medium-term follow-up studies was approximately 16 percent, with lower risk among "first-evers" compared to repeaters. There was a large variation in repetition rate. The proportion who committed suicide in medium-term follow-up studies was 2.8 percent and in long-term follow-up studies was 3.5 percent (weighted mean) with clearly higher proportions in the Nordic studies than in the studies from UK. Risk factors for attempted suicide were previous suicide attempt, alcohol and drug abuse, depression, schizophrenia, previous inpatient treatment, self-discharge before evaluation, sociopathy, unemployment, frequent change of address, hostility, and living alone. Several of the predictors are overlapping and most of them were already identified in early studies of factors predictive of repetition of suicide attempt. Predictors of suicide were male gender, increasing age, previous suicide attempt, serious suicide attempt, alcohol and substance abuse, somatic disease, mental illness, and planning of suicide attempt, high suicidal intent score, violent suicide attempt or suicide attempt with severe lethality, and ongoing or previous psychiatric treatment. In our follow-up study from Bispebjerg Hospital, we found that the risk of suicide during a ten-year follow-up period among patients admitted in 1980 after self-poisoning was 30 times greater than in the general population. We also found increased mortality by all other causes of death. Predictors of suicide were several previous suicide attempts, living alone and increasing age. There are not many randomised clinical trials of psychosocial interventions aiming to reduce risk of repetition among suicide attempters. A Cochrane review concluded that evidence was lacking to indicate the most effective forms of treatment for deliberate self-harm patients. A recent randomised controlled trial showed a positive influence of cognitive behavioural therapy on repetition rate. Our own quasi-experimental study of effectiveness of two weeks' inpatient treatment in a special unit of young persons who had severe suicidal thoughts or who had attempted suicide showed that risk of repetition was reduced in the intervention group, and that the intervention group obtained a significantly greater improvement in Beck's Depression Inventory, Hopelessness Scale, Rosenberg Self-Esteem Scale and CAGE-score. The study of emergency outreach indicates that there are many persons in the community that experience a suicidal crisis, and that this group is an important target group for psychiatric emergency outreach. In our study of registration and referral practice in Copenhagen Hospital Cooperation, we conclude that not all suicide attempts were registered as such in the National Patient Register - in fact, only 37 percent. It must be concluded that the quality of the Danish Patient Register must be improved with regard to registration of suicide attempt. We found that psychiatric evaluation was planned in relation to almost all suicide attempts, but that it must be recommended to pay attention to escorting patients to psychiatric emergency in order to ensure that the patient actually attends the planned consultation. We found that patients who were referred after psychiatric evaluation to psychiatric treatment at outpatient facilities only received the planned treatment in approximately two-thirds of the cases; therefore, like Hawton et al. [Hawton et al., 1998; Hawton et al., 1999], we recommend that outpatient facilities adopt an assertive approach to patients who have attempted suicide. Danish suicide research is strong, primarily due to the possibilities for linking complete national registers providing detailed data and large sample sizes for suicide research, which is so far unique for the Nordic countries. This, combined with skilful use of epidemiological methods, had resulted in a remarkable series of papers highlighting risk of suicide in different risk groups, risk factors and protective factors. This activity must continue. In this work it is important to be aware of limitations in naturalistic studies such as the risk of interchanging cause and effect and the necessity to carry out control for confounders. Meta-analysis is a strong tool for summing up results of previous research. Meta-analyses can be used in reporting the evidence for effectiveness of interventions, but also for determining risk or identifying risk factors. A meta-analysis of risk factors of repetition of suicide attempt has not been carried out, and the quality of the identified studies did not allow a formal meta-analysis. Large randomised clinical trials examining the effectiveness of interventions on reducing rate of suicide attempt and suicide should have high priority. Suicide is a major public health problem and should be given high priority with regard to prevention and research. (ABSTRACT TRUNCATED)

<h3>Importance</h3> Traumatic brain injuries (TBIs) can have serious long-term consequences, including psychiatric disorders. However, few studies have assessed the association between TBI and risk of suicide. <h3>Objective</h3> To examine the association between TBI and subsequent suicide. <h3>Design, Setting, and Participants</h3> Retrospective cohort study using nationwide registers covering 7 418 391 individuals (≥10 years) living in Denmark (1980-2014) with 164 265 624 person-years’ follow-up; 567 823 (7.6%) had a medical contact for TBI. Data were analyzed using Poisson regression adjusted for relevant covariates, including fractures not involving the skull, psychiatric diagnoses, and deliberate self-harm. <h3>Exposure</h3> Medical contacts for TBI recorded in the National Patient Register (1977-2014) as mild TBI (concussion), skull fracture without documented TBI, and severe TBI (head injuries with evidence of structural brain injury). <h3>Main Outcomes and Measures</h3> Suicide recorded in the Danish Cause of Death register until December 31, 2014. <h3>Results</h3> Of 34 529 individuals who died by suicide (mean age, 52 years [SD, 18 years]; 32.7% women; absolute rate 21 per 100 000 person-years [95% CI, 20.8-21.2]), 3536 (10.2%) had medical contact: 2701 with mild TBI, 174 with skull fracture without documented TBI, and 661 with severe TBI. The absolute suicide rate was 41 per 100 000 person-years (95% CI, 39.2-41.9) among those with TBI vs 20 per 100 000 person-years (95% CI, 19.7-20.1) among those with no diagnosis of TBI. The adjusted incidence rate ratio (IRR) was 1.90 (95% CI, 1.83-1.97). Compared with those without TBI, severe TBI (absolute rate, 50.8 per 100 000 person-years; 95% CI, 46.9-54.6) was associated with an IRR of 2.38 (95% CI, 2.20-2.58), whereas mild TBI (absolute rate, 38.6 per 100 000 person-years; 95% CI, 37.1-40.0), and skull fracture without documented TBI (absolute rate, 42.4 per 100 000 person-years; 95% CI, 36.1-48.7) had an IRR of 1.81 (95% CI, 1.74-1.88) and an IRR of 2.01 (95% CI, 1.73-2.34), respectively. Suicide risk was associated with number of medical contacts for TBI compared with those with no TBI contacts: 1 TBI contact, absolute rate, 34.3 per 100 000 person-years (95% CI, 33.0-35.7; IRR, 1.75; 95% CI, 1.68-1.83); 2 TBI contacts, absolute rate, 59.8 per 100 000 person-years (95% CI, 55.1-64.6; IRR, 2.31; 95% CI, 2.13-2.51); and 3 or more TBI contacts, absolute rate, 90.6 per 100 000 person-years (95% CI, 82.3-98.9; IRR, 2.59; 95% CI, 2.35-2.85; all<i>P</i> &lt; .001 for the IRR’s). Compared with the general population, temporal proximity since the last medical contact for TBI was associated with risk of suicide (<i>P</i>&lt;.001), with an IRR of 3.67 (95% CI, 3.33-4.04) within the first 6 months and an incidence IRR of 1.76 (95% CI, 1.67-1.86) after 7 years. <h3>Conclusions and Relevance</h3> In this nationwide registry-based retrospective cohort study individuals with medical contact for TBI, compared with the general population without TBI, had increased suicide risk.

<h2>Summary</h2><h3>Background</h3> People with mental disorders have higher mortality rates than the general population and more detailed estimates of mortality differences are needed to address this public health issue. We aimed to assess whether differences in cause-specific mortality between people with and without mental disorders have changed between 1995 and 2014 by quantifying life-years lost and assessing differences over time. <h3>Methods</h3> Using a cohort design, we linked nationwide population data from the Danish Civil Registration System to information about hospital contacts from the Psychiatric Central Research Register and deaths from the Danish Cause of Death register. All linked data sources contained longitudinal information covering all individuals aged 15–94 years living in Denmark between 1995 and 2014. We assessed cause-specific mortality differences using rate ratios and average life-years lost. <h3>Findings</h3> Between 1995 and 2014, 6 107 234 individuals (3 026 132 men and 3 081 102 women) aged 15–94 years were living in Denmark. The study population was observed over 89 216 177 person-years (men: 43 914 948; women 45 301 229). Cause-specific mortality rates were higher for people with mental disorders than those without (total mortality rate per 1000 person-years in men 27·1 <i>vs</i> 11·4, respectively, and in women 21·2 <i>vs</i> 11·0). When compared with individuals without mental disorders, men and women with mental disorders had 10·20 and 7·34 excess life-years lost, respectively. The largest cause-specific differences between those with and without mental disorders in terms of excess life-years lost were for respiratory diseases (men: 0·9; women: 1·4) and alcohol misuse (men: 2·8; women: 1·2). Between 1995 and 2014, we noted an increase in excess life-years lost for neoplasms (men: 0·7; women: 0·4), heart diseases (men: 1·2; women: 0·3), and respiratory diseases (men: 0·3; women: 0·2), and a decrease for suicide (men: −0·7; women: −0·5) and accidents (men: −0·9; women: −0·5). <h3>Interpretation</h3> By applying a novel approach, more precise estimates of life-years lost were obtained. The increase in excess mortality due to medical diseases and disorders among people with mental disorders emphasises the need for future interventions to address these aspects as well as the continued high shares of excess mortality due to alcohol misuse, suicide, and accidents. <h3>Funding</h3> The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH).

Bereavement after spousal suicide has been linked to mental disorders; however, a comprehensive assessment of the effect of spousal suicide is needed.To determine whether bereavement after spousal suicide was linked to an excessive risk of mental, physical, and social health outcomes when compared with the general population and spouses bereaved by other manners.This nationwide, register-based cohort study conducted in Denmark of 6.7 million individuals aged 18 years and older from 1980 to 2014 covered more than 136 million person-years and compared people bereaved by spousal suicide with the general population and people bereaved by other manners of death. Incidence rate ratios were calculated using Poisson regressions while adjusting for sociodemographic characteristics and the presence of mental and physical disorders.Mental disorders (any disorder, mood, posttraumatic stress disorder, anxiety, alcohol use disorders, drug use disorders, and self-harm); physical disorders (cancers, diabetes, sleep disorder, cardiovascular diseases, chronic lower respiratory tract diseases, liver cirrhosis, and spinal disc herniation); causes of mortality (all-cause, natural, unintentional, suicide, and homicide); social health outcomes; and health care use.The total study population included 3 491 939 men, 4814 of whom were bereaved by spousal suicide, and 3 514 959 women, 10 793 of whom were bereaved by spousal suicide. Spouses bereaved by a partner's suicide had higher risks of developing mental disorders within 5 years of the loss (men: incidence rate ratio, 1.8; 95% CI, 1.6-2.0; women: incidence rate ratio, 1.7; 95% CI, 1.6-1.8) than the general population. Elevated risks for developing physical disorders, such as cirrhosis and sleep disorders, were also noted as well as the use of more municipal support, sick leave benefits, and disability pension funds than the general population. Compared with spouses bereaved by other manners of death, those bereaved by suicide had higher risks for developing mental disorders (men: incidence rate ratio, 1.7; 95% CI, 1.5-1.9; women: incidence rate ratio, 2.0; 95% CI, 1.9-2.2), suicidal behaviors, mortality, and municipal support. Additionally, a higher level of mental health care use was noted.Exposure to suicide is stressful and affects the bereaved spouse on a broad range of outcomes. The excess risks of mental, physical, and social health outcomes highlight a need for more support directed toward spouses bereaved by suicide.

To assess the benefit and harm of exercise training in adults with clinical depression.The DEMO trial is a randomized pragmatic trial for patients with unipolar depression conducted from January 2005 through July 2007. Patients were referred from general practitioners or psychiatrists and were eligible if they fulfilled the International Classification of Diseases, Tenth Revision, criteria for unipolar depression and were aged between 18 and 55 years. Patients (N = 165) were allocated to supervised strength, aerobic, or relaxation training during a 4-month period. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)), the secondary outcome measure was the percentage of days absent from work during the last 10 working days, and the tertiary outcome measure was effect on cognitive abilities.At 4 months, the strength measured by 1 repetition maximum for chest press increased by a mean (95% CI) of 4.0 kg (0.8 to 7.2; p = .014) in the strength training group versus the relaxation group, and maximal oxygen uptake increased by 2.7 mL/kg/min (1.2 to 4.3; p = .001) in the aerobic group versus the relaxation group. At 4 months, the mean change in HAM-D(17) score was -1.3 (-3.7 to 1.2; p = .3) and 0.4 (-2.0 to 2.9; p = .3) for the strength and aerobic groups versus the relaxation group. At 12 months, the mean differences in HAM-D(17) score were -0.2 (-2.7 to 2.3; p = .8) and 0.6 (-1.9 to 3.1; p = .6) for the strength and aerobic groups versus the relaxation group. At 12 months, the mean differences in absence from work were -12.1% (-21.1% to -3.1%; p = .009) and -2.7% (-11.7% to 6.2%; p = .5) for the strength and aerobic groups versus the relaxation group. No statistically significant effect on cognitive abilities was found.Our findings do not support a biologically mediated effect of exercise on symptom severity in depressed patients, but they do support a beneficial effect of strength training on work capacity.(ClinicalTrials.gov) Identifier: NCT00103415.

Article AbstractObjective: Concomitant prescription of more than 1 antipsychotic agent (antipsychotic polypharmacy) in the treatment of schizophrenia is prevalent, although monotherapy is generally recommended. Mortality from natural causes is markedly increased in schizophrenia, and the role of polypharmacy remains controversial. The objective was to investigate if antipsychotic polypharmacy is associated with the excess mortality from natural causes among patients with schizophrenia. Method: A population-based nested case-control study was conducted using patient data from January 1, 1996, to December 31, 2005, obtained from central Danish registers. From the study population of 27,633 patients with ICD-8- and ICD-10-diagnosed schizophrenia or other mainly nonaffective psychoses, aged 18-53 years, we identified 193 cases who died of natural causes within a 2-year period and 1,937 age- and sex-matched controls. Current drug use was defined as at least 1 prescription filled within 90 days before the date of death or the index date. The data were analyzed by conditional logistic regression. Results: Risk of natural death did not increase with the number of concurrently used antipsychotic agents compared with antipsychotic monotherapy (no antipsychotics: adjusted odds ratio †‰=†‰1.48 ; 2 antipsychotics: OR†‰=†‰0.91 ; 3 or more antipsychotics: OR†‰=†‰1.16 ). Current use of benzodiazepine derivatives with long elimination half-lives (more than 24 hours) was associated with increased risk of natural death in patients with schizophrenia treated with antipsychotics (OR†‰=†‰1.78 ). Conclusions: Antipsychotic polypharmacy did not contribute to the excess mortality from natural causes in middle-aged patients with schizophrenia. The detected increased risk of death associated with benzodiazepines with long elimination half-lives calls for further clarification. Submitted: October 23, 2008; accepted January 2, 2009. Online ahead of print: November 3, 2009. Corresponding author: Lone Baandrup, MD, Centre for Neuropsychiatric Schizophrenia Research, Psychiatric Centre Glostrup, Copenhagen University Hospital, Glostrup, Nordre Ringvej 29-67, DK-2600 Glostrup, Denmark (lone.baandrup@cnsr.dk).

The ROAdmap for MEntal health Research in Europe project aimed to create an integrated European roadmap for mental health research. Leading mental health research experts across Europe have formulated consensus-based recommendations for future research within the public mental health field.Experts were invited to compile and discuss research priorities in a series of topic-based scientific workshops. In addition, a Delphi process was carried out to reach consensus on the list of research priorities and their rank order. Three web-based surveys were conducted. Nearly 60 experts were involved in the priority setting process.Twenty priorities for public mental health research were identified through the consensus process. The research priorities were divided into summary principles-encompassing overall recommendations for future public mental health research in Europe-and thematic research priorities, including area-specific top priorities on research topics and methods. The priorities represent three overarching goals mirroring societal challenges, that is, to identify causes, risk and protective factors for mental health across the lifespan; to advance the implementation of effective public mental health interventions and to reduce disparities in mental health.The importance of strengthening research on the implementation and dissemination of promotion, prevention and service delivery interventions in the mental health field needs to be emphasized. The complexity of mental health and its broader conceptualisation requires complementary research approaches and interdisciplinary collaboration to better serve the needs of the European population.

Life expectancy in patients with schizophrenia is reduced by 20 years for men and 15 years for women compared to the general population. About 60% of the excess mortality is due to physical illnesses, with cardiovascular disease being dominant. CHANGE was a randomized, parallel-group, superiority, multi-centre trial with blinded outcome assessment, testing the efficacy of an intervention aimed to improve cardiovascular risk profile and hereby potentially reduce mortality. A total of 428 patients with schizophrenia spectrum disorders and abdominal obesity were recruited and centrally randomized 1:1:1 to 12 months of lifestyle coaching plus care coordination plus treatment as usual (N=138), or care coordination plus treatment as usual (N=142), or treatment as usual alone (N=148). The primary outcome was 10-year risk of cardiovascular disease assessed post-treatment and standardized to age 60. At follow-up, the mean 10-year risk of cardiovascular disease was 8.4 ± 6.7% in the group receiving lifestyle coaching, 8.5 ± 7.5% in the care coordination group, and 8.0 ± 6.5% in the treatment as usual group (p=0.41). We found no intervention effects for any secondary or exploratory outcomes, including cardiorespiratory fitness, physical activity, weight, diet and smoking. In conclusion, the CHANGE trial did not support superiority of individual lifestyle coaching or care coordination compared to treatment as usual in reducing cardiovascular risk in patients with schizophrenia spectrum disorders and abdominal obesity.

To estimate and test associations between substance use disorders (SUDs) and both completed suicides and suicide attempts in a population with severe mental illness.Register-based cohort study with adjusted Cox regression of substance use disorders as time-varying covariates.Denmark.People born in Denmark since 1955 with a diagnosis of schizophrenia (n = 35 625), bipolar disorder (n = 9279), depression (n = 72 530) or personality disorder (n = 63 958).Treated SUDs of alcohol and illicit substances identified in treatment registers; suicide attempt identified in treatment registers; and completed suicides identified in the Cause of Death register. Covariates were sex and age at diagnosis.Having any SUD was associated with at least a threefold increased risk of completed suicide when compared with those having no SUD. Alcohol misuse was associated with an increased risk of completed suicide in all populations with hazard ratios (HR) between 1.99 [95% confidence interval (CI) = 1.44-2.74] and 2.70 (95% CI = 2.40-3.04). Other illicit substances were associated with a two- to threefold risk increase of completed suicide in all populations except bipolar disorder, and cannabis was associated with increased risk of attempted suicide only in people with bipolar disorder (HR = 1.86, 95% CI = 1.15-2.99). Alcohol and other illicit substances each displayed strong associations with attempted suicide, HR ranging from 3.11 (95% CI = 2.95-3.27) to 3.38 (95% CI = 3.24-3.53) and 2.13 (95% CI = 2.03-2.24) to 2.27 (95% CI = 2.12-2.43), respectively. Cannabis was associated with suicide attempts only in people with schizophrenia (HR = 1.11, 95% CI = 1.03-1.19).Substance use disorders are associated strongly with risk of completed suicides and suicide attempts in people with severe mental illness.

Numerous studies describe the occurrence of post-traumatic stress disorder following disasters, but less is known about the risk of major depression.To review the risk of depressive disorder in people surviving disasters and in soldiers returning from military deployment.A systematic literature search combined with reference screening identified 23 controlled epidemiological studies. We used random effects models to compute pooled odds ratios (ORs).The average OR was significantly elevated following all types of exposures: natural disaster OR = 2.28 (95% CI 1.30-3.98), technological disaster OR = 1.44 (95% CI 1.21-1.70), terrorist acts OR = 1.80 (95% CI 1.38-2.34) and military combat OR = 1.60 (95% CI 1.09-2.35). In a subset of ten high-quality studies OR was 1.41 (95% CI 1.06-1.87).Disasters and combat experience substantially increase the risk of depression. Whether psychological trauma per se or bereavement is on the causal path is unresolved.

Abstract Objective Gender differences in psychosis have been investigated, and the results have contributed to a better understanding of the disease, but many questions are unanswered. In clinical terms, women and men with psychosis differ in terms of access to social support, tendency of substance abuse, level of functioning and symptom patterns. We aimed to investigate how gender differences at onset of psychosis develop during the first 5 years of treatment. Method A total of 578 patients with a first-episode psychosis in the schizophrenia spectrum were included in the Danish OPUS trial – a randomized clinical trial comparing 2 years of intensive early-intervention programme with standard treatment. All patients were assessed with validated instruments at inclusion, and after 2 and 5 years. Data were analysed for significant gender differences. Results Males have significantly higher levels of negative symptoms at all times, and are more likely to live alone and suffer from substance abuse. Females reach higher levels of social functioning at follow-up, and show a greater tendency to be employed or in education than males. Markedly more women than men live with children. More women than men reach a state of recovery and are more compliant with medication. Conclusion There are significant gender differences at 2- and 5-year follow-up in this large cohort of first-episode psychotic patients. Males and females show different symptomatology and different levels of social functioning.

<h3>Importance</h3> Findings suggest that infections might be linked to the development of psychiatric disorders and suicidal behavior. Large-scale studies are needed to investigate the effect of infection on the risk of suicide. <h3>Objective</h3> To estimate the association between hospitalization with infection and the risk of death by suicide. <h3>Design, Setting, and Participants</h3> Nationwide, population-based, prospective cohort study with more than 149 million person-years of follow-up. Data were analyzed with survival analysis techniques and were adjusted for sex, age, calendar period, cohabitation status, socioeconomic status, and the Charlson Comorbidity Index. Individual data were drawn from Danish longitudinal registers. A total of 7.22 million individuals 15 years or older living in Denmark between January 1, 1980, and December 31, 2011, were observed during a 32-year follow-up period. <h3>Main Outcomes and Measures</h3> The risk of death by suicide was identified in the Danish Cause of Death Register. Incidence rate ratios (IRRs) and accompanying 95% CIs were used as measures of relative risk. <h3>Results</h3> In 7 221 578 individuals (3 601 653 men and 3 619 925 women) observed for a total of 149 061 786 person-years, 32 683 suicides were observed during the follow-up period. Among the suicides, 7892 (24.1%) individuals had previously been diagnosed as having an infection during a hospitalization. Hospitalization with infection was linked to an elevated risk of suicide, with an IRR of 1.42 (95% CI, 1.38-1.46) compared with those without prior infection. Dose-response relationships were observed with respect to the number of hospital contacts for different infections. For example, having 7 or more infections was linked to an IRR of 2.90 (95% CI, 2.14-3.93). The number of days of treatment for infections was associated with an elevated risk of suicide in a dose-response relationship. More than 3 months of hospital treatment was linked to an IRR of 2.38 (95% CI, 2.05-2.76). The population-attributable risk associated with hospitalization with infection accounted for 10.1% of suicides. <h3>Conclusions and Relevance</h3> An increased risk of death by suicide was found among individuals hospitalized with infection in prospective and dose-response relationships. These findings indicate that infections may have a relevant role in the pathophysiological mechanisms of suicidal behavior.

Background Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort. Methods This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders. Findings Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012–0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040–0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy. Interpretation The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. Funding Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.

To assess the benefits and harms of exercise in patients with depression.Systematic review DATA SOURCES: Bibliographical databases were searched until 20 June 2017.Eligible trials were randomised clinical trials assessing the effect of exercise in participants diagnosed with depression. Primary outcomes were depression severity, lack of remission and serious adverse events (eg, suicide) assessed at the end of the intervention. Secondary outcomes were quality of life and adverse events such as injuries, as well as assessment of depression severity and lack of remission during follow-up after the intervention.Thirty-five trials enrolling 2498 participants were included. The effect of exercise versus control on depression severity was -0.66 standardised mean difference (SMD) (95% CI -0.86 to -0.46; p<0.001; grading of recommendations assessment, development and evaluation (GRADE): very low quality). Restricting this analysis to the four trials that seemed less affected of bias, the effect vanished into -0.11 SMD (-0.41 to 0.18; p=0.45; GRADE: low quality). Exercise decreased the relative risk of no remission to 0.78 (0.68 to 0.90; p<0.001; GRADE: very low quality). Restricting this analysis to the two trials that seemed less affected of bias, the effect vanished into 0.95 (0.74 to 1.23; p=0.78). Trial sequential analysis excluded random error when all trials were analysed, but not if focusing on trials less affected of bias. Subgroup analyses found that trial size and intervention duration were inversely associated with effect size for both depression severity and lack of remission. There was no significant effect of exercise on secondary outcomes.Trials with less risk of bias suggested no antidepressant effects of exercise and there were no significant effects of exercise on quality of life, depression severity or lack of remission during follow-up. Data for serious adverse events and adverse events were scarce not allowing conclusions for these outcomes.The protocol was published in the journal Systematic Reviews: 2015; 4:40.

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk. There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk. Protein-truncating variants (PTVs) are likely to modify gene function and have been linked to hundreds of Mendelian disorders.1Amberger J.S. Bocchini C.A. Schiettecatte F. Scott A.F. Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders.Nucleic Acids Res. 2015; 43: D789-D798Crossref PubMed Scopus (1122) Google Scholar, 2Landrum M.J. Lee J.M. Benson M. Brown G. Chao C. Chitipiralla S. Gu B. Hart J. Hoffman D. Hoover J. et al.ClinVar: public archive of interpretations of clinically relevant variants.Nucleic Acids Res. 2016; 44: D862-D868Crossref PubMed Scopus (1522) Google Scholar However, the impact of PTVs on complex traits has been limited by the available sample size of whole-exome sequencing studies (WESs).3Zuk O. Schaffner S.F. Samocha K. Do R. Hechter E. Kathiresan S. Daly M.J. Neale B.M. Sunyaev S.R. Lander E.S. Searching for missing heritability: designing rare variant association studies.Proc. Natl. Acad. Sci. USA. 2014; 111: E455-E464Crossref PubMed Scopus (408) Google Scholar Here, we assembled whole-exome sequencing data from 100,296 individuals, drawing from a combination of cohort and case/control disease studies with phenotypic information on a total of 13 quantitative traits and 10 diseases (Tables S1–S3). We used a common pipeline to process, annotate, and analyze the data (see Supplemental Material and Methods and Figure S1 for principal components plots). Ethical committees for each study approved all procedures and all subjects provided written informed consent (or legal guardian consent and subject assent). We began by focusing our analysis on PTVs that occur in a set of 3,172 PTV-intolerant (PI) genes (see Table S4 for all gene sets used in this study). Our motivation for focusing on the PI-PTVs was two-fold. First, this gene class was identified through an unbiased approach that leveraged the observed frequency distribution in ExAC4Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6556) Google Scholar without relying on information from model organisms or in vitro experiments. Second, PI-PTVs have been shown to associate with early-onset neurodevelopmental and psychiatric disorders and are likely to result in reproductively disadvantageous phenotypes.5Genovese G. Fromer M. Stahl E.A. Ruderfer D.M. Chambert K. Landén M. Moran J.L. Purcell S.M. Sklar P. Sullivan P.F. et al.Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia.Nat. Neurosci. 2016; 19: 1433-1441Crossref PubMed Scopus (277) Google Scholar, 6Robinson E.B. St Pourcain B. Anttila V. Kosmicki J.A. Bulik-Sullivan B. Grove J. Maller J. Samocha K.E. Sanders S.J. Ripke S. et al.iPSYCH-SSI-Broad Autism GroupGenetic risk for autism spectrum disorders and neuropsychiatric variation in the general population.Nat. Genet. 2016; 48: 552-555Crossref PubMed Scopus (242) Google Scholar, 7Deciphering Developmental Disorders StudyPrevalence and architecture of de novo mutations in developmental disorders.Nature. 2017; 542: 433-438Crossref PubMed Scopus (765) Google Scholar To focus on those variants that are most likely to be subject to purifying selection, we considered only rare (allele frequency < 0.1%) and ultra-rare (observed in fewer than 1 in 201,176 individuals) variants (Supplemental Material and Methods). After excluding participants diagnosed with a psychiatric or neurodevelopmental disorder, we observed an average of 7.72 and 0.30 rare PTVs per individual, across all genes and in PI genes, respectively (Figure 1A); one or more ultra-rare PI-PTV was observed in 11% of the individuals. The number and frequency of rare variants differs across populations, reflecting the degree of selection compounded by recent demography, including bottlenecks, split times, and migration between populations.8Mathieson I. McVean G. Demography and the age of rare variants.PLoS Genet. 2014; 10: e1004528Crossref PubMed Scopus (56) Google Scholar The ratio of deleterious to neutral alleles per individual increases as humans migrated out of Africa, consistent with less efficient negative selection against deleterious variants and serial founder effects that reduce the effective population size.9Henn B.M. Botigué L.R. Peischl S. Dupanloup I. Lipatov M. Maples B.K. Martin A.R. Musharoff S. Cann H. Snyder M.P. et al.Distance from sub-Saharan Africa predicts mutational load in diverse human genomes.Proc. Natl. Acad. Sci. USA. 2016; 113: E440-E449Crossref PubMed Scopus (131) Google Scholar Conditional on a variant being ultra-rare, we observe a higher ratio of PTVs to synonymous variants (Figure 1B); recently arisen ultra-rare variants have had less time to be purged by negative selection, which is further magnified in populations that have undergone a recent bottleneck. For example, we observed a higher ratio among Ashkenazi Jewish and Finnish populations as compared to non-Finnish Europeans, reflecting the more recent population-specific bottlenecks.10Ostrer H. Skorecki K. The population genetics of the Jewish people.Hum. Genet. 2013; 132: 119-127Crossref PubMed Scopus (68) Google Scholar, 11Lim E.T. Würtz P. Havulinna A.S. Palta P. Tukiainen T. Rehnström K. Esko T. Mägi R. Inouye M. Lappalainen T. et al.Sequencing Initiative Suomi (SISu) ProjectDistribution and medical impact of loss-of-function variants in the Finnish founder population.PLoS Genet. 2014; 10: e1004494Crossref PubMed Scopus (250) Google Scholar We tested the association between a burden of PI-PTVs and the 13 traits and 10 disease diagnoses (Figure 2) by performing study-specific and ethnicity-specific linear or logistic regression analysis adjusting for potential confounders such as overall mutation rate (Table S5). The results of these separate analyses were then meta-analyzed (Supplemental Material and Methods). We used an experiment-wise p value threshold of 2 × 10−3 to account for multiple testing (0.05/23 traits tested). Among the quantitative traits, we found that carriers of at least one rare PI-PTV had fewer years of education (−2.2 months, p = 4 × 10−4), as we have previously reported,12Ganna A. Genovese G. Howrigan D.P. Byrnes A. Kurki M. Zekavat S.M. Whelan C.W. Kals M. Nivard M.G. Bloemendal A. et al.Ultra-rare disruptive and damaging mutations influence educational attainment in the general population.Nat. Neurosci. 2016; 19: 1563-1565Crossref PubMed Scopus (51) Google Scholar were shorter (−0.2 cm, p = 3 × 10−4), and were younger (−3.7 months, p = 2 × 10−7). To ensure the robustness of the age (at enrollment) result, we performed a series of quality control analyses to guard against the impact of technical confounders or specific study designs that might bias the results. We first confirm that the signal was not observed among PTVs in non-PI genes and synonymous variants in PI genes, our negative controls (Figure S2). We further found that the effect was consistent across ethnicities and study cohorts (Figure S3), when INDELs and SNPs were considered separately, when mutations possibly caused by cytosine deamination (C>T or G>A) were excluded, and when a highly stringent QC was used (Figure S4). Similarly, the association did not change after adjusting for eight QC metrics capturing most of the sample properties (Figure S5). Although we could not exclude the impact of unmeasured confounder, we find this result consistent with reduced survival, detrimental health, or decreased study participation over time among PI-PTVs carriers. If reduced survival or detrimental health effects drive this association, we see it as a signature of viability selection, overall in the population. Analyses with time at death as the outcome will be needed to confirm the interpretation of this finding. We then focused on dichotomous traits (Figure 2). We observed significant associations with all psychiatric disorders that were tested: intellectual disability (ID) (odds ratio [OR] = 1.7, p = 4 × 10−8), autism (OR = 1.3, p = 1 × 10−14), schizophrenia (OR = 1.2, p = 5 × 10−8), ADHD (OR = 1.2, p = 5 × 10−10), and bipolar disorder (OR = 1.2, p = 8 × 10−4). We did not, however, find PI-PTV burden to be associated with later-onset, non-brain-related diseases such as type 2 diabetes, early-onset myocardial infarction, inflammatory bowel disease, ulcerative colitis, or Crohn disease. Across all significantly associated phenotypes, the effect size was stronger among the subset of ultra-rare PI-PTV carriers, confirming that rarer PTVs are, on average, more deleterious. The association with these five neurodevelopmental/psychiatric disorders and three quantitative traits was observed only for PI-PTVs and not for PTVs in non-PI genes nor for synonymous variants in PI genes. These results suggest that the association to PI-PTVs is not driven by population stratification or technical bias (Figure S6). Our approach so far focuses on assuming that all PI-PTVs act on the phenotype in the same direction, that is, they are all either protective or risk conferring. We relaxed this hypothesis, allowing rare PI-PTVs to have different directions as well as different magnitudes of effects, and repeated these tests using SKAT.13Wu M.C. Lee S. Cai T. Li Y. Boehnke M. Lin X. Rare-variant association testing for sequencing data with the sequence kernel association test.Am. J. Hum. Genet. 2011; 89: 82-93Abstract Full Text Full Text PDF PubMed Scopus (1573) Google Scholar We did not identify any additional associations (Figure S7), suggesting that PI genes do not account for a substantial fraction of variability in the traits for which no PTV burden was identified. Further, the observed burden of PI-PTVs for neurodevelopmental/psychiatric disorders, height, educational attainment, and age suggests that the majority of those PI genes that have an effect, do so in the same direction. Although case ascertainment bias reduces the power of detecting protective variants, this is not the case for continuous traits like height. We also evaluated whether damaging missense variants, which are on average more common and less severely deleterious than PTVs, showed a similar signal. Damaging missense variants have been associated with complex disorders such as coronary heart disease and inflammatory bowel disease.14Stitziel N.O. Stirrups K.E. Masca N.G. Erdmann J. Ferrario P.G. König I.R. Weeke P.E. Webb T.R. Auer P.L. Schick U.M. et al.Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia InvestigatorsCoding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease.N. Engl. J. Med. 2016; 374: 1134-1144Crossref PubMed Scopus (340) Google Scholar, 15Luo Y. de Lange K.M. Jostins L. Moutsianas L. Randall J. Kennedy N.A. Lamb C.A. McCarthy S. Ahmad T. Edwards C. et al.Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.Nat. Genet. 2017; 49: 186-192Crossref PubMed Scopus (102) Google Scholar We found an independent signal for damaging missense variants in PI genes for all disorders and traits that were also associated with PI-PTVs. Furthermore, the strength of the association increased as a function of the number of prediction algorithms that confidently classified a missense variant as “damaging” (Figure S8), suggesting that these missense mutations are similar to PTVs in biological effect, potentially abrogating gene function. We note that this effect was particularly strong for ultra-rare variants, reinforcing the observation that variant frequency is a marker of selection and aids in the identification of pathogenic damaging missense variation.16Cavalli-Sforza L.L. Population structure and human evolution.Proc. R. Soc. Lond. B Biol. Sci. 1966; 164: 362-379Crossref PubMed Scopus (253) Google Scholar, 17Price G.R. Selection and covariance.Nature. 1970; 227: 520-521Crossref PubMed Scopus (1124) Google Scholar Given the high degree of shared comorbidities across neurodevelopmental/psychiatric disorders, we leveraged information from the Danish National Psychiatric registry to evaluate whether the signal was driven by a specific disorder or shared across multiple disorders. Individuals with multiple neurodevelopmental/psychiatric disorders, and especially those with ID, showed a stronger enrichment of PI-PTVs (Figure S9). Nevertheless, among those without comorbidities, the signal remained significant and remarkably similar across disorders (OR = 1.12, 1.15, 1.21, 1.18 for schizophrenia, bipolar, autism, and ADHD, respectively; Cochran’s Q test for heterogeneity p = 0.282). We further found that carriers of ultra-rare PI-PTVs had earlier onset of ADHD (−4.0 months, p = 0.008; Table S6). However, this was partially explained by the fact that individuals with earlier diagnosis of ADHD were also more likely to be diagnosed with ID (14.7 versus 15.5 years for individuals with ADHD with and without ID, t test p value = 0.009). Indeed, when we considered ADHD-affected case subjects without major comorbidities, the effect was attenuated (−2.9 months, p = 0.12). Finally, in control subjects with none of these psychiatric diagnoses, we still observed a significant association with the broader ICD-10 category of mental, behavioral, and neurodevelopmental disorders, suggesting that PI-PTVs influence the broader cognitive spectrum (Table S7). Since previous studies have shown a higher rate of PI de novo PTVs in autism-affected females as compared to males,18Krumm N. Turner T.N. Baker C. Vives L. Mohajeri K. Witherspoon K. Raja A. Coe B.P. Stessman H.A. He Z.X. et al.Excess of rare, inherited truncating mutations in autism.Nat. Genet. 2015; 47: 582-588Crossref PubMed Scopus (363) Google Scholar, 19Kosmicki J.A. Samocha K.E. Howrigan D.P. Sanders S.J. Slowikowski K. Lek M. Karczewski K.J. Cutler D.J. Devlin B. Roeder K. et al.Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.Nat. Genet. 2017; 49: 504-510Crossref PubMed Scopus (194) Google Scholar we wondered whether sex played a role here. In this study, however, we did not have parent-offspring subjects needed to distinguish de novo variants from those that have recently arisen in the population, the latter being the majority of observed rare variants. This would potentially dilute the sex-specific effect if it is in fact a property of de novo variants but not of rare variants more generally. We found both weak and insignificant differences between males and females in the effect of PI-PTVs on four neurodevelopmental/psychiatric disorders (Table S8). Interestingly, we did not observe differences in ADHD-affected males and females, in contrast with the hypothesis that affected females might be enriched for rare deleterious variants.20Taylor M.J. Lichtenstein P. Larsson H. Anckarsater H. Greven C.U. Ronald A. Is There a Female Protective Effect Against Attention-Deficit/Hyperactivity Disorder? Evidence From Two Representative Twin Samples.J Am Acad Child Adolesc Psychiatry. 2016; 55: 504-512 e502Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar We cannot exclude that differences in the diagnostic criteria used in these European studies compared to those of previous studies, which were mostly conducted in the U.S., might explain these results. We also assessed whether the observed burden of PTVs was specific to PI genes or whether such a burden could be identified for other gene sets that are likely to contain functionally relevant genes. First, we examined other experimental and literature-based gene sets linked to severe phenotypes. Specifically, we considered all genes (1) reported in ClinVar,2Landrum M.J. Lee J.M. Benson M. Brown G. Chao C. Chitipiralla S. Gu B. Hart J. Hoffman D. Hoover J. et al.ClinVar: public archive of interpretations of clinically relevant variants.Nucleic Acids Res. 2016; 44: D862-D868Crossref PubMed Scopus (1522) Google Scholar (2) that resulted in lethal or subviable phenotypes in mice,21Dickinson M.E. Flenniken A.M. Ji X. Teboul L. Wong M.D. White J.K. Meehan T.F. Weninger W.J. Westerberg H. Adissu H. et al.International Mouse Phenotyping ConsortiumJackson LaboratoryInfrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS)Charles River LaboratoriesMRC HarwellToronto Centre for PhenogenomicsWellcome Trust Sanger InstituteRIKEN BioResource CenterHigh-throughput discovery of novel developmental phenotypes.Nature. 2016; 537: 508-514Crossref PubMed Scopus (637) Google Scholar (3) that were required for proliferation and survival in a human cancer cell line,22Wang T. Birsoy K. Hughes N.W. Krupczak K.M. Post Y. Wei J.J. Lander E.S. Sabatini D.M. Identification and characterization of essential genes in the human genome.Science. 2015; 350: 1096-1101Crossref PubMed Scopus (946) Google Scholar and (4) were categorized as haploinsufficient by ClinGen (Table S4 and Supplemental Material and Methods). Except for the haploinsufficient genes, which showed a significantly stronger association with autism alone, none of the other gene sets tested showed the PTV burden that was captured by PI genes (Figure S10). This suggests that the degree of natural selection against PTVs in a gene is indeed an important indicator of whether such PTVs are likely to be implicated as strong effects for neurodevelopmental/psychiatric disorders, height, educational attainment, and age. It also highlights that observed associations are not simply reflecting an aggregate signal from known Mendelian disorders. Indeed, we could not detect significant association for any of the traits considered in this analysis when focusing on just ClinVar genes. We reasoned that a single variant approach, rather than a gene-based test, might provide increased resolution. We considered all high-quality ClinVar variants (0.76 on average per individual) and a set of variants deemed to be recessive lethal (0.03) (Supplemental Material and Methods). Carriers of these variants were not enriched in any of the disorders or traits examined here (Table S9). Second, we examined whether results from GWASs conducted on the same phenotypes as those included in this study could implicate genes containing an aggregate PTV burden. We used DEPICT23Pers T.H. Karjalainen J.M. Chan Y. Westra H.J. Wood A.R. Yang J. Lui J.C. Vedantam S. Gustafsson S. Esko T. et al.Genetic Investigation of ANthropometric Traits (GIANT) ConsortiumBiological interpretation of genome-wide association studies using predicted gene functions.Nat. Commun. 2015; 6: 5890Crossref PubMed Scopus (457) Google Scholar to link genome-wide significant hits to candidate genes (Table S10 and Supplemental Material and Methods) and, within each GWAS-derived gene set, we studied the association between rare PTVs and the phenotypes using the SKAT test. GWAS-derived gene-sets captured associations between rare PTVs and different classes of lipids (Figure 3 and Table S11). For example, the association between rare PTVs and HDL cholesterol was captured by gene sets derived from GWASs of HDL (p = 2 × 10−9), total cholesterol (p = 3 × 10−8), and triglycerides (p = 4 × 10−9), but not by those of coronary heart diseases (p = 0.25), consistent with previous observations about non-causality of HDL cholesterol on coronary heart diseases.24Voight B.F. Peloso G.M. Orho-Melander M. Frikke-Schmidt R. Barbalic M. Jensen M.K. Hindy G. Hólm H. Ding E.L. Johnson T. et al.Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.Lancet. 2012; 380: 572-580Abstract Full Text Full Text PDF PubMed Scopus (1648) Google Scholar The inclusion of both rare damaging missense and PTVs resulted in additional signal co-localization between inflammatory bowel disease, early-onset myocardial infarction, and the corresponding GWAS-derived gene sets. However, it appeared that all these signals were being driven by well-known genes, involved in rare familial forms of these diseases. Specifically, when Mendelian lipid genes and NOD2 were removed from the cardiovascular and inflammatory bowel disease-related GWAS gene sets, respectively, no signal remained (Figure S11). This might reflect a lack of power (despite this being the largest WES study for the majority of the traits), inaccurate links between genome-wide significant hits and the corresponding candidate genes or PTVs, and common variants acting on partially distinct pathways. Nevertheless, we observed similar results when including SNPs below genome-wide significance to increase power and when using different methods to link SNPs with corresponding candidate genes to increase precision, including gene-based testing25de Leeuw C.A. Mooij J.M. Heskes T. Posthuma D. MAGMA: generalized gene-set analysis of GWAS data.PLoS Comput. Biol. 2015; 11: e1004219Crossref PubMed Scopus (1126) Google Scholar and eQTL mapping (Figure S11 and Supplemental Material and Methods). The choice of the 10 diseases and 13 quantitative traits included in the main analysis was driven by data availability and power considerations but was not truly unbiased. Therefore, we leveraged national population health registries to increase the scope of disorders we could examine. These well-studied and validated registries26Ludvigsson J.F. Andersson E. Ekbom A. Feychting M. Kim J.L. Reuterwall C. Heurgren M. Olausson P.O. External review and validation of the Swedish national inpatient register.BMC Public Health. 2011; 11: 450Crossref PubMed Scopus (3086) Google Scholar, 27Sund R. Quality of the Finnish Hospital Discharge Register: a systematic review.Scand. J. Public Health. 2012; 40: 505-515Crossref PubMed Scopus (721) Google Scholar include diagnostic codes from 14,117 individuals (n = 8,493 from Finland and 5,624 from Sweden), recorded between 1968 and 2015 (Table S12). Individuals with psychiatric disorders were excluded from our analyses. To maximize the validity of the diagnoses, we used a curated list of disease definitions aggregating related ICD codes (Table S13). We studied the association between rare PI-PTVs and 101 diseases with at least 50 case subjects, using a survival analysis model. We identified an association (multi-testing significance threshold = 0.05/101; 5 × 10−4) with chronic kidney failure (hazard ratio = 1.9, p = 3 × 10−6; number of case subjects = 120; Figure S12). The association was strong among the Finnish data and only significant when considering ultra-rare PI-PTVs in the Swedish data (Table S14). We speculated that this association might reflect a burden of underlying comorbidities that were too rare to be included in this analysis. To evaluate epidemiological associations, we extended our analysis to 28,709 Finnish individuals that were not exome sequenced but were linked to the registries. We found that individuals with chronic kidney failure also have a higher rate of cardiovascular-related comorbidities, as well as skin infections, kidney cancer, and other abnormalities of the renal system (Table S15). Therefore, it is challenging to determine whether it is the chronic kidney failure or some more rare comorbid condition that drives the association with PI-PTVs. Nevertheless, five PI-PTVs in Finnish individuals with chronic kidney failure were in genes involved in Mendelian-type disorders characterized by renal or endocrine abnormalities (ARNT2, COL4A1, DMXL2, FBN1, and NNT; Supplemental Material and Methods). We also examined whether the association between PI-PTVs and diminished cognition and detrimental health would result in a higher number of hospital visits, counting the number of in-patient visits associated with a unique ICD codes. In both the Swedish and Finnish datasets, we observed a significant increase in the rate of hospital visits with a greater burden of PI-PTVs (+7.6% per additional PI-PTV, p = 0.0002). We used different strategies to model the outcome and observed similar results (Table S16 and Figure S13). By aggregating WES data on more than 100,000 individuals for 23 different traits and disorders, we have gained insight into the role of PTVs in conferring risk for these conditions. First, PTVs occurring in PI genes had a remarkably similar effect on autism, schizophrenia, bipolar disorder, and ADHD. The majority of this signal was driven by ultra-rare PI-PTVs and we observed only a marginal additional contribution of non-ultra-rare PTVs with allele frequency < 0.1% (Figure S14). The observed effects of PI-PTVs on psychiatric disorders were not driven by major underlying comorbidities. This suggests that these PI-PTVs as a whole are likely to be pleiotropic, influencing some core intermediate phenotypes that relate to risk across many psychiatric disorders. Nevertheless, we could consider only “bulk” pleiotropy, which is the combined impact of PTVs in PI genes, and we are not powered to detect whether single variants have disease-specific effects. Further, this burden suggests that individual PI genes will be eventually discovered conclusively for each of these disorders, not just autism, but that such associations will need to be interpreted in the light of this shared effect across disorders. The strong enrichment of PI-PTVs in individuals with neurodevelopmental/psychiatric disorders does not exclude the existence of non-PI genes involved in the etiology of these disorders. These genes, however, are more likely to have weaker and, possibly, trait-specific effect. Second, we detected a significant association between PI-PTVs and decreased human height. In contrast to this, a recent large-scale study using the exome chip has shown a similar numbers of height-increasing and height-decreasing rare variants.28Marouli E. Graff M. Medina-Gomez C. Lo K.S. Wood A.R. Kjaer T.R. Fine R.S. Lu Y. Schurmann C. Highland H.M. et al.EPIC-InterAct ConsortiumCHD Exome+ ConsortiumExomeBP ConsortiumT2D-Genes ConsortiumGoT2D Genes ConsortiumGlobal Lipids Genetics ConsortiumReproGen ConsortiumMAGIC InvestigatorsRare and low-frequency coding variants alter human adult height.Nature. 2017; 542: 186-190Crossref PubMed Scopus (358) Google Scholar This discrepancy could be because, by using a more stringent frequency cut-off and focusing on a subset of genes likely to cause early-onset severe disease, we effectively considered variants related to a burden of (incompletely) penetrant Mendelian-type disorders, often characterized by reduced growth. Such an interpretation is consistent with a tighter link to directional selection on stronger impact mutations for human height. Third, we systematically compared the co-localization of signal between GWAS-candidate genes and rare PTVs. We found few overlaps (cardiovascular-related traits, inflammatory bowel disease) which, we revealed, were entirely driven by a few genes previously identified by both GWASs and WES studies. Other traits did not show any overlap. Schizophrenia, for example, which is highly enriched for PI-PTVs, did not show overlap with GWAS candidate genes. Even among traits where genes with low-frequency coding variants have been previously identified by exome-chip-based studies, such as height and systolic blood pressure, we found no substantial rare PTVs enrichment. These results suggest that the relationship between GWAS signal and rare coding variants is not always straightforward, and that, when interpreting WES data, other complementary approaches such as those that integrate population genetic models and large sample resources might be more suitable to nominate gene sets of interest. The degree of overlap, and therefore the most effective strategy to identify pathogenic variants, is likely to depend on the selective pressure shaping the genetic architecture of the trait under investigation. Moreover, it cannot be overlooked that individuals carrying rare PTVs in genes implicated by common variant-based approaches might present phenotypic outcomes that deviate from those under investigation. Finally, it is interesting to notice that, while PTVs tend to have a consistent directional effect within a PI gene, this is not the case for GWAS-derived gene sets, where most of signals could be captured only by assuming heterogeneity in effect direction (Supplemental Material and Methods). In conclusion, in this large WES study, we showed that PI genes are well suited to capture the impact of rare to ultra-rare PTVs on the cognitive, behavioral, and developmental spectra. This is less the case for major later-onset complex traits with modest effect on reproductive fitness. Strategies to prioritize gene sets relevant for these traits would need to consider the role that relaxed selective pressure has been playing in shaping the frequency distribution of disease-causing PTVs. Benjamin M. Neale is a member of the scientific advisory board at Deep Genomics and a paid consultant at Camp4 Therapeutics Corporation, Merck & Co., and Avanir Pharmaceuticals. A.G. is supported by the Knut and Alice Wallenberg Foundation (2015.0327) and the Swedish Research Council (2016-00250). This study was supported by grants from the National Human Genome Research Institute (U54 HG003067, R01 HG006855), the National Institute of Mental Health (1U01MH105666-01, 1R01MH101244-02, R01 MH077139, and RC2 MH089905), the National Institute of Diabetes and Digestive and Kidney Disease (1U54DK105566-02), the Stanley Center for Psychiatric Research, the Alexander and Margaret Stewart Trust, and the Sylvan C. Herman Foundation. V.S. was supported by the Finnish Foundation for Cardiovascular Research. We have made the code and variants used in the paper available at https://github.com/andgan/ultra_rare_pheno_spectrum. We are extremely committed to data sharing. However, we recognize that due to national regulation, not all individual-level data and phenotypes can be shared using dbGap. Specifically, access to the Danish and Finnish phenotypic and genetic data can be obtained only by Danish and Finnish national institutions. Information about getting access to the Danish data can be obtained at http://ipsych.au.dk/about-ipsych/. Access to the Finnish data can be obtained at https://www.thl.fi/en/web/thl-biobank/for-researchers. We are happy to help other researchers with information to simplify the application process to obtain these datasets. All the remaining datasets are available via dbGap, as follows. Migen: phs000814.v1.p1, phs000902.v1.p1, phs000917.v1.p1, phs000883.v1.p1, phs001058.v1.p1, phs000806.v1.p1, phs001000.v1.p1, phs000990.v1.p1, phs000916.v1.p1, phs001101.v1.p1; T2D-GENES/GoT2D/SIGMA: phs001099, phs001098, phs000849, phs001097, phs001096, phs001095, phs001093, phs001100, phs001102, phs000840; Swedish Schizophrenia: phs000473.v2.p2; IBD: phs001076.v1.p1. Download .pdf (2.32 MB) Help with pdf files Document S1. Figures S1–S14 and Supplemental Material and Methods Download .xlsx (.33 MB) Help with xlsx files Spreadsheet S2. Tables S1–S3 and S5–S16 Download .xlsx (5.56 MB) Help with xlsx files Table S4. All Gene Sets Used in the Study Codes and variants, https://github.com/andgan/ultra_rare_pheno_spectrumdbGaP, https://www.ncbi.nlm.nih.gov/gapiPSYCH, http://ipsych.au.dk/about-ipsychTHL Biobank, https://www.thl.fi/en/web/thl-biobank/for-researchers

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10−12) that replicates in an independent population (Preplication = 3.27 × 10−3, Pmeta-analysis = 9.09 × 10−12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD. The study reports a genome-wide significant locus for cannabis use disorder, replicating in an independent cohort, and implicates CHRNA2, which encodes an acetylcholine receptor subunit, in the disorder by analyses of genetically regulated gene expression.

Abstract Purpose: To estimate the risk of schizophrenia in adulthood among children and adolescents with ADHD compared to the background population. Subjects/materials and methods: Two hundred and eight youths with ADHD (183 boys; 25 girls) were followed prospectively. Diagnoses of schizophrenia were obtained from The Danish Psychiatric Central Register. The relative risk (RR) of schizophrenia for cases with ADHD, compared to the normal population, was calculated as risk ratios. Hazard ratios (HR's) by Cox regression were calculated in the predictor analyses. Results: Mean age for ADHD cases at follow-up was 31.1 years. Schizophrenia diagnoses were given to 3.8% of these cases. Compared to the general population, RR of schizophrenia in cases with ADHD was 4.3 (95% CI 1.9–8.57). Discussion and conclusion: This prospective follow-up study found children with ADHD to be at higher risk of later schizophrenia than controls. If replicated, these results warrant increased focus on the possible emergence symptoms of schizophrenia or schizophreniform psychosis during clinical follow-up of patients with ADHD.

The hippocampal volume is reduced in patients with major depression. Exercise leads to an increased hippocampal volume in schizophrenia and in healthy old adults. The effect of exercise on hippocampal volume is potentially mediated by brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin like growth factor 1 (IGF-1). The aim of this trial was to assess the effect of an aerobic exercise intervention on hippocampal volume and serum BDNF, VEGF, and IGF-1 in patients with major depression. Patients were randomized to an aerobic exercise intervention (n=41) or a control condition (n=38). Both interventions consisted of three supervised sessions per week during a three months period. Post-intervention the increase in maximal oxygen uptake was 3.90 ml/kg/min (SD 5.1) in the aerobic exercise group and 0.95 ml/kg/min (SD 6.2) in the control group (p=0.03). The hippocampal volume, BDNF, VEGF, or IGF-1 did not differ between the two groups. Post-hoc we found a positive association between change in hippocampal volume and verbal memory (Rho=0.27; p=0.05) and change in hippocampal volume and depressive symptoms (Rho=0.30; p=0.03). Participation was low in both groups corresponding to an average participation of one session per week. Despite a significant increase in maximal oxygen uptake, a pragmatic exercise intervention did not increase hippocampal volume or resting levels of neurotrophines in out-patients with mild to moderate major depression. Trial identifier: ClinicalTrials.gov (NCT00695552)

The effect of referring patients from a clinical setting to a pragmatic exercise intervention for depressive symptoms, cognitive function, and metabolic variables has yet to be determined.Outpatients with major depression (DSM-IV) were allocated to supervised aerobic or stretching exercise groups during a three months period. The primary outcome was the Hamilton depression score (HAM-D(17)). Secondary outcomes were cognitive function, cardiovascular risk markers, and employment related outcomes.56 participants were allocated to the aerobic exercise intervention versus 59 participants to the stretching exercise group. Post intervention the mean difference between groups was -0.78 points on the HAM-D(17) (95% CI -3.2 to 1.6; P = .52). At follow-up, the participants in the aerobic exercise group had higher maximal oxygen uptake (mean difference 4.4 l/kg/min; 95% CI 1.7 to 7.0; P = .001) and visuospatial memory on Rey's Complex Figure Test (mean difference 3.2 points; 95% CI 0.9 to 5.5; P = .007) and lower blood glucose levels (mean difference 0.2 mmol/l; 95% CI 0.0 to 0.5; P = .04) and waist circumference (mean difference 2.2 cm; 95% CI 0.3 to 4.1; P = .02) compared with the stretching exercise group.The results of this trial does not support any antidepressant effect of referring patients with major depression to a three months aerobic exercise program. Due to lower recruitment than anticipated, the trial was terminated prior to reaching the pre-defined sample size of 212 participants; therefore the results should be interpreted in that context. However, the DEMO-II trial does suggest that an exercise program for patients with depression offer positive short-term effects on maximal oxygen uptake, visuospatial memory, fasting glucose levels, and waist circumference.ClinicalTrials.gov NCT00695552.

Suicide is a serious public health problem, with more than 800,000 deaths taking place worldwide each year. Mental disorders are associated with increased risk of suicide. In schizophrenia and other psychotic disorders, the lifetime risk of suicide death is estimated to be 5.6%. The risk is particularly high during the first year of the initial contact with mental health services, being almost twice as high as in the later course of the illness. The most consistently reported risk factor for suicide among people with psychotic disorders is a history of attempted suicide and depression. Suicide risk in psychosis in Denmark decreased over time, most likely because of improved quality of inpatient and outpatient services. There is a high proportion of young people with first-episode psychosis who attempted suicide before their first contact with mental health services. This finding suggests that the mortality rates associated with psychotic disorders may be underreported because of suicide deaths taking place before first treatment contact. However, currently, no data exist to confirm or refute this hypothesis. Attempted suicide can be an early warning sign of later psychotic disorder. Data from different studies indicate that the risk of suicide attempt during the first year of treatment is as high as 10%. The most important risk factors for attempted suicide after the first contact are young age, female sex, suicidal plans, and a history of suicide attempt. Early intervention services are helpful in first-episode psychosis, and staff members should, in collaboration with the patients, monitor the risk of suicide and develop and revise crisis plans.

Many psychological treatments have shown effect on reducing self-harm in adults with borderline personality disorder. There is a need of brief psychotherapeutical treatment alternative for suicide prevention in specialized outpatient clinics.The DiaS trial was designed as a pragmatic single-center, two-armed, parallel-group observer-blinded, randomized clinical superiority trial. The participants had at least two criteria from the borderline personality disorder diagnosis and a recent suicide attempt (within a month). The participants were offered 16 weeks of dialectical behavior therapy (DBT) versus up to 16 weeks of collaborative assessment and management of suicidality (CAMS) treatment. The primary composite outcome was the number of participants with a new self-harm (nonsuicidal self-injury [NSSI] or suicide attempt) at week 28 from baseline. Other exploratory outcomes were: severity of borderline symptoms, depressive symptoms, hopelessness, suicide ideation, and self-esteem.At 28 weeks, the number of participants with new self-harm in the DBT group was 21 of 57 (36.8%) versus 12 of 51 (23.5%) in the CAMS treatment (OR: 1.90; 95% CI: 0.80-4.40; P = .14). When assessing the effect of DBT versus CAMS treatment on the individual components of the primary outcome, we observed no significant differences in the number of NSSI (OR: 1.60; 95% CI: 0.70-3.90; P = .31) or number of attempted suicides (OR: 2.24; 95% CI: 0.80-7.50; P = .12).In adults with borderline personality traits and disorder and a recent suicide attempt, DBT does not seem superior compared with CAMS for reduction of number of self-harm or suicide attempts. However, further randomized clinical trials may be needed.

To compare the effects of five years of specialised early intervention (SEI) treatment for first episode schizophrenia spectrum disorder with the standard two years of SEI plus three years of treatment as usual.Randomised, superiority, parallel group trial with blinded outcome assessment. Randomisation was centralised and computerised with concealed randomisation sequence carried out at an external site.Participants were recruited from six OPUS teams in Denmark between 2009 and 2012. OPUS teams provide SEI treatment to all patients diagnosed with a schizophrenia spectrum disorder in Denmark.400 participants (51% women) with a mean age of 25.6 (standard deviation 4.3) were randomised to five years of SEI (experimental intervention; n=197) or to two years of SEI plus three years of treatment as usual (control; n=203).OPUS treatment consists of three core elements-modified assertive community treatment, family involvement, and social skill training-with a patient-case manager ratio of no more than 12:1. For participants randomised to five years of OPUS treatment, the treatment was largely unchanged. Participants randomised to the control group were mostly referred to community health centres after two years of SEI treatment.Follow-up assessments were conducted five years after start of OPUS treatment. Primary outcome was negative symptoms measured on the scale for assessment of negative symptoms (avolition-apathy, anhedonia, alogia, and affective blunting). Secondary outcomes were remission of both negative and psychotic symptoms, psychotic symptoms, suicidal ideation, substance abuse, compliance with medical treatment, adherence with treatment, client satisfaction, days in hospital care, and labour market affiliation.Levels of negative symptoms did not differ between the intervention group and control group (1.72 v 1.81 points; estimated mean difference -0.10 (95% confidence interval -0.33 to 0.13), P=0.39). Participants receiving five years of OPUS treatment were more likely to remain in contact with specialised mental health services (90.4% v 55.6%, P<0.001), had higher client satisfaction (estimated mean difference 2.57 points (95% confidence interval 1.36 to 3.79), P<0.001), and had a stronger working alliance (estimated mean difference 5.56 points (95% confidence interval 2.30 to 8.82), P=0.001) than the control group.This trial tests SEI treatment for up to five years for patients with first episode schizophrenia spectrum disorder; previous trials have found treatment effects for programmes lasting from one to three years. The prolonged SEI treatment had few effects, which could be due to the high level of treatment provided to control participants and the late start of specialised treatment.Trial registration Clinicaltrial.gov NCT00914238.

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. We quantified neonatal methylomic variation in 1263 infants—of whom ~ 50% went on to subsequently develop ASD—using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of − 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.

Background Although deliberate self-harm is a strong predictor of suicide, evidence for effective interventions is missing. The aim of this study was to examine whether psychosocial therapy after self-harm was linked to lower risks of repeated self-harm, suicide, and general mortality. Methods In this matched cohort study all people who, after deliberate self-harm, received a psychosocial therapy intervention at suicide prevention clinics in Denmark during 1992–2010 were compared with people who did not receive the psychosocial therapy intervention after deliberate self-harm. We applied propensity score matching with a 1:3 ratio and 31 matching factors, and calculated odds ratios for 1, 5, 10, and 20 years of follow-up. The primary endpoints were repeated self-harm, death by suicide, and death by any cause. Findings 5678 recipients of psychosocial therapy (followed up for 42·828 person-years) were matched with 17 034 individuals with no psychosocial therapy in a 1:8 ratio. During 20 year follow-up, 937 (16·5%) recipients of psychosocial therapy repeated the act of self-harm, and 391 (6·9%) died, 93 (16%) by suicide. The psychosocial therapy intervention was linked to lower risks of self-harm than was no psychosocial therapy (odds ratio [OR] 0·73, 95% CI 0·65–0·82) and death by any cause (0·62, 0·47–0·82) within a year. Long-term effects were identified for repeated self-harm (0·84, 0·77–0·91; absolute risk reduction [ARR] 2·6%, 1·5–3·7; numbers needed to treat [NNT] 39, 95% CI 27–69), deaths by suicide (OR 0·75, 0·60–0·94; ARR 0·5%, 0·1–0·9; NNT 188, 108–725), and death by any cause (OR 0·69, 0·62–0·78; ARR 2·7%, 2·0–3·5; NNT 37, 29–52), implying that 145 self-harm episodes and 153 deaths, including 30 deaths by suicide, were prevented. Interpretation Our findings show a lower risk of repeated deliberate self-harm and general mortality in recipients of psychosocial therapy after short-term and long-term follow-up, and a protective effect for suicide after long-term follow-up, which favour the use of psychosocial therapy interventions after deliberate self-harm. Funding Danish Health Insurance Foundation; the Research Council of Psychiatry, Region of Southern Denmark; the Research Council of Psychiatry, Capital Region of Denmark; and the Strategic Research Grant from Health Sciences, Capital Region of Denmark.

Homelessness remains a societal problem. Compiled evidence of predictors for becoming homeless and exiting homelessness might be used to inform policy-makers and practitioners in their work to reduce homeless-related problems. We examined individual-level predictors for becoming homeless and exiting homelessness by searching PubMed, EMBASE, PsycINFO, and Web of Science up to January 2018. Becoming homeless and exiting homelessness were the outcomes. Observational studies with comparison groups from high-income countries were included. The Newcastle Ottawa Quality Assessment Scale was used for bias assessment. Random effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). We included 116 independent studies of risk factors for becoming homeless and 18 for exiting homelessness. We found evidence of adverse life events as risk factors for homelessness, e.g., physical abuse (OR 2.9, 95% CI 1.8-4.4) and foster care experiences (3.7, 1.9-7.3). History of incarceration (3.6, 1.3-10.4), suicide attempt (3.6, 2.1-6.3), and psychiatric problems, especially drug use problems (2.9, 1.5-5.1), were associated with increased risk of homelessness. The heterogeneity was substantial in most analyses (I2 > 90%). Female sex (1.5, 1.1-1.9; I2 = 69%) and having a partner (1.7, 1.3-2.1; I2 = 40%) predicted higher chances whereas relationship problems (0.6, 0.5-0.8), psychotic disorders (0.4, 0.2-0.8; I2 = 0%), and drug use problems (0.7, 0.6-0.9; I2 = 0%) reduced the chances for exiting homelessness. In conclusion, sociodemographic factors, adverse life events, criminal behaviour, and psychiatric problems were individual-level predictors for becoming homeless and/or exiting homelessness. Focus on individual-level vulnerabilities and early intervention is needed. PROSPERO registration number: CRD42014013119 .