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...

People with severe mental illness (SMI) -schizophrenia, bipolar disorder and major depressive disorder -appear at risk for cardiovascular disease (CVD), but a comprehensive meta-analysis is lacking. We conducted a large-scale meta-analysis assessing the prevalence and incidence of CVD; coronary heart disease; stroke, transient ischemic attack or cerebrovascular disease; congestive heart failure; peripheral vascular disease; and CVD-related death in SMI patients (N53,211,768) versus controls (N5113,383,368) (92 studies). The pooled CVD prevalence in SMI patients (mean age 50 years) was 9.9% (95% CI: 7.4-13.3). Adjusting for a median of seven confounders, patients had significantly higher odds of CVD versus controls in cross-sectional studies (odds ratio, OR51.53, 95% CI: 1.27-1.83; 11 studies), and higher odds of coronary heart disease (OR51.51, 95% CI: 1.47-1.55) and cerebrovascular disease (OR51.42, 95% CI: 1.21-1.66). People with major depressive disorder were at increased risk for coronary heart disease, while those with schizophrenia were at increased risk for coronary heart disease, cerebrovascular disease and congestive heart failure. Cumulative CVD incidence in SMI patients was 3.6% (95% CI: 2.7-5.3) during a median follow-up of 8.4 years (range 1.8-30.0). Adjusting for a median of six confounders, SMI patients had significantly higher CVD incidence than controls in longitudinal studies (hazard ratio, HR51.78, 95% CI: 1.60-1.98; 31 studies). The incidence was also higher for coronary heart disease (HR51.54, 95% CI: 1.30-1.82), cerebrovascular disease (HR51.64, 95% CI: 1.26-2.14), congestive heart failure (HR52.10, 95% CI: 1.64-2.70), and CVDrelated death (HR51.85, 95% CI: 1.53-2.24). People with major depressive disorder, bipolar disorder and schizophrenia were all at increased risk of CVD-related death versus controls. CVD incidence increased with antipsychotic use (p50.008), higher body mass index (p50.008) and higher baseline CVD prevalence (p50.03) in patients vs. controls. Moreover, CVD prevalence (p50.007), but not CVD incidence (p50.21), increased in more recently conducted studies. This large-scale meta-analysis confirms that SMI patients have significantly increased risk of CVD and CVD-related mortality, and that elevated body mass index, antipsychotic use, and CVD screening and management require urgent clinical attention.Key words: Cardiovascular disease, severe mental illness, schizophrenia, bipolar disorder, major depression, coronary heart disease, cerebrovascular disease, congestive heart failure, premature mortality (World Psychiatry 2017;16:163-180) People with severe mental illness (SMI) -including schizophrenia, bipolar disorder, major depressive disorder, and their related spectrum disorders -have a life expectancy shortened of 10-17.5 years compared to the general population 1,2 . While suicide explains some of this reduced life expectancy 3 , it is now established that physical diseases account for the overwhelming majority of premature mortality 4,5 . Among physical conditions, c...

Objective To conduct a systematic review and meta‐analysis of studies that measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls (HCs). Method The PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched up until May 30, 2016. Effect sizes were estimated with random‐effects models. Result Eighty‐two studies comprising 3212 participants with MDD and 2798 HCs met inclusion criteria. Peripheral levels of interleukin‐6 (IL‐6), tumor necrosis factor (TNF)‐alpha, IL‐10, the soluble IL‐2 receptor, C‐C chemokine ligand 2, IL‐13, IL‐18, IL‐12, the IL‐1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs, whereas interferon‐gamma levels were lower in MDD (Hedge's g = −0.477, P = 0.043). Levels of IL‐1β, IL‐2, IL‐4, IL‐8, the soluble IL‐6 receptor (sIL‐6R), IL‐5, CCL‐3, IL‐17, and transforming growth factor‐beta 1 were not significantly altered in individuals with MDD compared to HCs. Heterogeneity was large (I2: 51.6–97.7%), and sources of heterogeneity were explored (e.g., age, smoking status, and body mass index). Conclusion Our results further characterize a cytokine/chemokine profile associated with MDD. Future studies are warranted to further elucidate sources of heterogeneity, as well as biosignature cytokines secreted by other immune cells.

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.

This meta-analysis points to a reciprocal interaction between depression and frailty in older adults. Specifically, each condition is associated with an increased prevalence and incidence of the other, and may be a risk factor for the development of the other. However, further prospective investigations are warranted.

The pathogenesis of frailty and the role of inflammation is poorly understood. We examined the evidence considering the relationship between inflammation and frailty through a systematic review and meta-analysis. A systematic literature search of papers providing data on inflammatory biomarkers and frailty was carried out in major electronic databases from inception until May 2016. From 1856 initial hits, 35 studies (32 cross-sectional studies n=3232 frail, n=11,483 pre-frail and n=8522 robust, and 563 pre-frail+robust; 3 longitudinal studies n=3402 participants without frailty at baseline) were meta-analyzed. Cross-sectional studies reported that compared to 6757 robust participants, both 1698 frail (SMD=1.00, 95%CI: 0.40-1.61) and 8568 pre-frail (SMD=0.33, 95%CI: 0.04-0.62) participants had significantly higher levels of C-reactive protein (CRP). Frailty (n=1057; SMD=1.12, 95%CI: 0.27-2.13) and pre-frailty (n=4467; SMD=0.56, 95%CI: 0.00-1.11) were associated with higher serum levels of interleukin-6 compared to people who were robust (n=2392). Frailty and pre-frailty were also significantly associated with elevated white blood cell and fibrinogen levels. In three longitudinal studies, higher serum CRP (OR=1.06, 95%CI: 0.78-1.44,) and IL-6 (OR=1.19, 95%CI: 0.87-1.62) were not associated with frailty. In conclusion, frailty and pre-frailty are associated with higher inflammatory parameters and in particular CRP and IL-6. Further longitudinal studies are needed.

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