Executive SummaryThe poor physical health of people with mental illness is a multi-faceted, transdiagnostic, and global problem. Physical health disparities are observed across the entire spectrum of mental illnesses, in low, middle-and high-income countries. This stems from both a heightened risk of physical diseases in people with mental illness, along with their reduced access to adequate healthcare. The high rates of physical comorbidities (and typically-poor clinical management of this) drastically reduces life expectancy, and also increases the personal, social and economic burden of illness across the lifespan.This Commission has brought together an international team of researchers, clinicians, and key stakeholders from various backgrounds and professionally / personally-relevant experience, in order to summarize advances in understanding on this topic, and present clear directions for health promotion, clinical care and future research. The breadth and multifactorial nature of physical health disparities across the range of mental health diagnoses poses an almost limitless number of potential considerations. Therefore, rather than attempting to cover all of the different possible combinations of physical-mental comorbidities individually, the aim of this Commission was to: (i) establish highlypertinent aspects of physical health-related morbidity and mortality which apply transdiagnostically, (ii) highlight the common modifiable factors driving these disparities, (iii) present actions and initiatives for health policy and clinical services to address these issues, and (iv) identify promising areas for future research towards discovering novel solutions. This was addressed across 5 different Parts of the Commission: Parts 1 and 2 determined the scope, priorities and key targets for physical health improvement across multiple mental illnesses. Parts 3, 4 and 5 discussed emerging strategies and produced recommendations for improving physical health outcomes in people with mental illness. Leaders and contributors for each Part are shown in the Appendix (pg.1) . Part 1: 'Its more than premature mortality'Part 1 identified almost 100 systematic reviews/meta-analyses examining the prevalence of physical comorbidities in mental illness. Around 70% of the meta-research focused on cardiometabolic diseases; consistently reporting that mental illnesses were associated with 1.4-to 2-fold increased risk for obesity, diabetes and cardiovascular diseases compared to the general population. Although mostly studied in 'severe mental illness' ('SMI', and particularly psychotic disorders), the prevalence of cardiometabolic diseases was similarly elevated across a broad range of other diagnoses, including substance use disorders (SUDs), and 'common mental disorders' ('CMDs', such as depression and anxiety). Part 2: Key modifiable factors in health behaviours and health servicesPart 2 built on the findings of Part 1 with a hierarchal evidence synthesis of modifiable risk factors for physical diseases in mental illness. The bu...

Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11–34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7–16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9–25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14–29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15–23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17–48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20–41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20–34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20–33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21–46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.

People with severe mental illness (schizophrenia, bipolar disorder or major depressive disorder) die up to 15 years prematurely due to chronic somatic comorbidities. Sedentary behavior and low physical activity are independent yet modifiable risk factors for cardiovascular disease and premature mortality in these people. A comprehensive meta-analysis exploring these risk factors is lacking in this vulnerable population. We conducted a metaanalysis investigating sedentary behavior and physical activity levels and their correlates in people with severe mental illness. Major electronic databases were searched from inception up to April 2017 for articles measuring sedentary behavior and/or physical activity with a self-report questionnaire or an objective measure (e.g., accelerometer). Random effects meta-analyses and meta-regression analyses were conducted. Sixty-nine studies were included (N535,682; 39.5% male; mean age 43.0 years). People with severe mental illness spent on average 476.0 min per day (95% CI: 407.3-545.4) being sedentary during waking hours, and were significantly more sedentary than age-and gender-matched healthy controls (p50.003). Their mean amount of moderate or vigorous physical activity was 38.4 min per day (95% CI: 32.0-44.8), being significantly lower than that of healthy controls (p50.002 for moderate activity, p<0.001 for vigorous activity). People with severe mental illness were significantly less likely than matched healthy controls to meet physical activity guidelines (odds ratio 5 1.5; 95% CI: 1.1-2.0, p<0.001, I 2 595.8). Lower physical activity levels and non-compliance with physical activity guidelines were associated with male gender, being single, unemployment, fewer years of education, higher body mass index, longer illness duration, antidepressant and antipsychotic medication use, lower cardiorespiratory fitness and a diagnosis of schizophrenia. People with bipolar disorder were the most physically active, yet spent most time being sedentary. Geographical differences were detected, and inpatients were more active than outpatients and those living in the community. Given the established health benefits of physical activity and its low levels in people with severe mental illness, future interventions specifically targeting the prevention of physical inactivity and sedentary behavior are warranted in this population.Key words: Physical activity, sedentary behavior, severe mental illness, schizophrenia, bipolar disorder, major depressive disorder, physical activity guidelines, cardiovascular disease, premature mortality (World Psychiatry 2017;16:308-315) People with severe mental illness (schizophrenia, bipolar disorder or major depressive disorder) have higher levels of somatic comorbidities and premature mortality than the general population 1-3 . A recent meta-analysis 4 documented that mortality rates are approximately two to three times increased in these people. The higher premature mortality rates are largely attributable to cardiovascular disease 5 .In the general populati...

Bipolar disorders are chronic and recurrent disorders that affect >1% of the global population. Bipolar disorders are leading causes of disability in young people as they can lead to cognitive and functional impairment and increased mortality, particularly from suicide and cardiovascular disease. Psychiatric and nonpsychiatric medical comorbidities are common in patients and might also contribute to increased mortality. Bipolar disorders are some of the most heritable psychiatric disorders, although a model with gene-environment interactions is believed to best explain the aetiology. Early and accurate diagnosis is difficult in clinical practice as the onset of bipolar disorder is commonly characterized by nonspecific symptoms, mood lability or a depressive episode, which can be similar in presentation to unipolar depression. Moreover, patients and their families do not always understand the significance of their symptoms, especially with hypomanic or manic symptoms. As specific biomarkers for bipolar disorders are not yet available, careful clinical assessment remains the cornerstone of diagnosis. The detection of hypomanic symptoms and longtudinal clinical assessment are crucial to differentiate a bipolar disorder from other conditions. Optimal early treatment of patients with evidence-based medication (typically mood stabilizers and antipsychotics) and psychosocial strategies is necessary.

Newer generation antidepressant drugs (ADs) are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents. In this critical review, we evaluated the literature on adverse events, tolerability and safety of selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, bupropion, mirtazapine, trazodone, agomelatine, vilazodone, levomilnacipran and vortioxetine. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms (nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances (heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system disturbances (lowering of seizure threshold, extrapyramidal side effects, cognitive disturbances), sweating, sleep disturbances, affective disturbances (apathy, switches, paradoxical effects), ophthalmic manifestations (glaucoma, cataract) and hyperprolactinemia. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. Other areas of concern involve suicidality, safety in overdose, discontinuation syndromes, risks during pregnancy and breast feeding, as well as risk of malignancies. Thus, the rational selection of ADs should consider the potential benefits and risks, likelihood of responsiveness to the treatment option and vulnerability to adverse events. The findings of this review should alert the physician to carefully review the appropriateness of AD prescription on an individual basis and to consider alternative treatments if available.

As the COVID-19 pandemic has largely increased the utilization of telehealth, mobile mental health technologies -such as smartphone apps, virtual reality, chatbots, and social media -have also gained attention. These digital health technologies offer the potential of accessible and scalable interventions that can augment traditional care. In this paper, we provide a comprehensive update on the overall field of digital psychiatry, covering three areas. First, we outline the relevance of recent technological advances to mental health research and care, by detailing how smartphones, social media, artificial intelligence and virtual reality present new opportunities for "digital phenotyping" and remote intervention. Second, we review the current evidence for the use of these new technological approaches across different mental health contexts, covering their emerging efficacy in self-management of psychological well-being and early intervention, along with more nascent research supporting their use in clinical management of long-term psychiatric conditions -including major depression; anxiety, bipolar and psychotic disorders; and eating and substance use disorders -as well as in child and adolescent mental health care. Third, we discuss the most pressing challenges and opportunities towards real-world implementation, using the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework to explain how the innovations themselves, the recipients of these innovations, and the context surrounding innovations all must be considered to facilitate their adoption and use in mental health care systems. We conclude that the new technological capabilities of smartphones, artificial intelligence, social media and virtual reality are already changing mental health care in unforeseen and exciting ways, each accompanied by an early but promising evidence base. We point out that further efforts towards strengthening implementation are needed, and detail the key issues at the patient, provider and policy levels which must now be addressed for digital health technologies to truly improve mental health research and treatment in the future.

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis.

Background Prospective cohorts have suggested that physical activity (PA) can decrease the risk of incident anxiety. However, no meta‐analysis has been conducted. Aims To examine the prospective relationship between PA and incident anxiety and explore potential moderators. Methods Searches were conducted on major databases from inception to October 10, 2018 for prospective studies (at least 1 year of follow‐up) that calculated the odds ratio (OR) of incident anxiety in people with high PA against people with low PA. Methodological quality was assessed using the Newcastle‐Ottawa Scale (NOS). A random‐effects meta‐analysis was conducted and heterogeneity was explored using subgroup and meta‐regression analysis. Results Across 14 cohorts of 13 unique prospective studies (N = 75,831, median males = 50.1%) followed for 357,424 person‐years, people with high self‐reported PA (versus low PA) were at reduced odds of developing anxiety (adjusted odds ratio [AOR] = 0.74; 95% confidence level [95% CI] = 0.62, 0.88; crude OR = 0.80; 95% CI = 0.69, 0.92). High self‐reported PA was protective against the emergence of agoraphobia (AOR = 0.42; 95% CI = 0.18, 0.98) and posttraumatic stress disorder (AOR = 0.57; 95% CI = 0.39, 0.85). The protective effects for anxiety were evident in Asia (AOR = 0.31; 95% CI = 0.10, 0.96) and Europe (AOR = 0.82; 95% CI = 0.69, 0.97); for children/adolescents (AOR = 0.52; 95% CI = 0.29, 0.90) and adults (AOR = 0.81; 95% CI = 0.69, 0.95). Results remained robust when adjusting for confounding factors. Overall study quality was moderate to high (mean NOS = 6.7 out of 9). Conclusion Evidence supports the notion that self‐reported PA can confer protection against the emergence of anxiety regardless of demographic factors. In particular, higher PA levels protects from agoraphobia and posttraumatic disorder.