The psychosis metabolic risk calculator (PsyMetRiC) for young people with psychosis: International external validation and site-specific recalibration in two independent European samples.

Background: Cardiometabolic dysfunction is common in young people with psychosis. Recently, the Psychosis Metabolic Risk Calculator (PsyMetRiC) was developed and externally validated in the UK, predicting up-to six-year risk of metabolic syndrome (MetS) from routinely collected data. The full-model includes age, sex, ethnicity, body-mass index, smoking status, prescription of metabolically-active antipsychotic medication, high-density lipoprotein, and triglyceride concentrations; the partial-model excludes biochemical predictors. Methods: To move toward a future internationally-useful tool, we externally validated PsyMetRiC in two independent European samples. We used data from the PsyMetab (Lausanne, Switzerland) and PAFIP (Cantabria, Spain) cohorts, including participants aged 16-35y without MetS at baseline who had 1-6y follow-up. Predictive performance was assessed primarily via discrimination (C-statistic), calibration (calibration plots), and decision curve analysis. Site-specific recalibration was considered. Findings: We included 1024 participants (PsyMetab n=558, male=62%, outcome prevalence=19%, mean follow-up=2.48y; PAFIP n=466, male=65%, outcome prevalence=14%, mean follow-up=2.59y). Discrimination was better in the full- compared with partial-model (PsyMetab=full-model C=0.73, 95% C.I., 0.68-0.79, partial-model C=0.68, 95% C.I., 0.62-0.74; PAFIP=full-model C=0.72, 95% C.I., 0.66-0.78; partial-model C=0.66, 95% C.I., 0.60-0.71). As expected, calibration plots revealed varying degrees of miscalibration, which recovered following site-specific recalibration. PsyMetRiC showed net benefit in both new cohorts, more so after recalibration. Interpretation: The study provides evidence of PsyMetRiC's generalizability in Western Europe, although further local and international validation studies are required. In future, PsyMetRiC could help clinicians internationally to identify young people with psychosis who are at higher cardiometabolic risk, so interventions can be directed effectively to reduce long-term morbidity and mortality. Funding: NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); The Wellcome Trust (201486/Z/16/Z); Swiss National Research Foundation (320030-120686, 324730- 144064, and 320030-173211); The Carlos III Health Institute (CM20/00015, FIS00/3095, PI020499, PI050427, and PI060507); IDIVAL (INT/A21/10 and INT/A20/04); The Andalusian Regional Government (A1-0055-2020 and A1-0005-2021); SENY Fundacion Research (2005-0308007); Fundacion Marques de Valdecilla (A/02/07, API07/011); Ministry of Economy and Competitiveness and the European Fund for Regional Development (SAF2016-76046-R and SAF2013-46292-R).For the Spanish and French translation of the abstract see Supplementary Materials section.

Development and external validation of the Psychosis Metabolic Risk Calculator (PsyMetRiC): a cardiometabolic risk prediction algorithm for young people with psychosis.

BACKGROUND: Young people with psychosis are at high risk of developing cardiometabolic disorders; however, there is no suitable cardiometabolic risk prediction algorithm for this group. We aimed to develop and externally validate a cardiometabolic risk prediction algorithm for young people with psychosis. METHODS: We developed the Psychosis Metabolic Risk Calculator (PsyMetRiC) to predict up to 6-year risk of incident metabolic syndrome in young people (aged 16-35 years) with psychosis from commonly recorded information at baseline. We developed two PsyMetRiC versions using the forced entry method: a full model (including age, sex, ethnicity, body-mass index, smoking status, prescription of a metabolically active antipsychotic medication, HDL concentration, and triglyceride concentration) and a partial model excluding biochemical results. PsyMetRiC was developed using data from two UK psychosis early intervention services (Jan 1, 2013, to Nov 4, 2020) and externally validated in another UK early intervention service (Jan 1, 2012, to June 3, 2020). A sensitivity analysis was done in UK birth cohort participants (aged 18 years) who were at risk of developing psychosis. Algorithm performance was assessed primarily via discrimination (C statistic) and calibration (calibration plots). We did a decision curve analysis and produced an online data-visualisation app. FINDINGS: 651 patients were included in the development samples, 510 in the validation sample, and 505 in the sensitivity analysis sample. PsyMetRiC performed well at internal (full model: C 0·80, 95% CI 0·74-0·86; partial model: 0·79, 0·73-0·84) and external validation (full model: 0·75, 0·69-0·80; and partial model: 0·74, 0·67-0·79). Calibration of the full model was good, but there was evidence of slight miscalibration of the partial model. At a cutoff score of 0·18, in the full model PsyMetRiC improved net benefit by 7·95% (sensitivity 75%, 95% CI 66-82; specificity 74%, 71-78), equivalent to detecting an additional 47% of metabolic syndrome cases. INTERPRETATION: We have developed an age-appropriate algorithm to predict the risk of incident metabolic syndrome, a precursor of cardiometabolic morbidity and mortality, in young people with psychosis. PsyMetRiC has the potential to become a valuable resource for early intervention service clinicians and could enable personalised, informed health-care decisions regarding choice of antipsychotic medication and lifestyle interventions. FUNDING: National Institute for Health Research and Wellcome Trust.

Longitudinal association between CRP levels and risk of psychosis: a meta-analysis of population-based cohort studies.

Meta-analyses of cross-sectional studies suggest that patients with psychosis have higher circulating levels of C-reactive protein (CRP) compared with healthy controls; however, cause and effect is unclear. We examined the prospective association between CRP levels and subsequent risk of developing a psychotic disorder by conducting a systematic review and meta-analysis of population-based cohort studies. Databases were searched for prospective studies of CRP and psychosis. We obtained unpublished results, including adjustment for age, sex, body mass index, smoking, alcohol use, and socioeconomic status and suspected infection (CRP > 10 mg/L). Based on random effect meta-analysis of 89,792 participants (494 incident cases of psychosis at follow-up), the pooled odds ratio (OR) for psychosis for participants with high (>3 mg/L), as compared to low (≤3 mg/L) CRP levels at baseline was 1.50 (95% confidence interval [CI], 1.09-2.07). Evidence for this association remained after adjusting for potential confounders (adjusted OR [aOR] = 1.31; 95% CI, 1.03-1.66). After excluding participants with suspected infection, the OR for psychosis was 1.36 (95% CI, 1.06-1.74), but the association attenuated after controlling for confounders (aOR = 1.23; 95% CI, 0.95-1.60). Using CRP as a continuous variable, the pooled OR for psychosis per standard deviation increase in log(CRP) was 1.11 (95% CI, 0.93-1.34), and this association further attenuated after controlling for confounders (aOR = 1.07; 95% CI, 0.90-1.27) and excluding participants with suspected infection (aOR = 1.07; 95% CI, 0.92-1.24). There was no association using CRP as a categorical variable (low, medium or high). While we provide some evidence of a longitudinal association between high CRP (>3 mg/L) and psychosis, larger studies are required to enable definitive conclusions.

Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study.

BACKGROUND: About every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis. METHODS: This study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n = 110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n = 1058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n = 1143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples. RESULTS: Network analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria. Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods. CONCLUSIONS: Genetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.

Longitudinal Trends in Childhood Insulin Levels and Body Mass Index and Associations With Risks of Psychosis and Depression in Young Adults.

Importance: Cardiometabolic disorders often occur concomitantly with psychosis and depression, contribute to high mortality rates, and are detectable from the onset of the psychiatric disorders. However, it is unclear whether longitudinal trends in cardiometabolic traits from childhood are associated with risks for adult psychosis and depression. Objective: To examine whether specific developmental trajectories of fasting insulin (FI) levels and body mass index (BMI) from early childhood were longitudinally associated with psychosis and depression in young adults. Design, Setting, and Participants: A cohort study from the Avon Longitudinal Study of Parents and Children, a prospective study including a population-representative British cohort of 14 975 individuals, was conducted using data from participants aged 1 to 24 years. Body mass index and FI level data were used for growth mixture modeling to delineate developmental trajectories, and associations with psychosis and depression were assessed. The study was conducted between July 15, 2019, and March 24, 2020. Exposures: Fasting insulin levels were measured at 9, 15, 18, and 24 years, and BMI was measured at 1, 2, 3, 4, 7, 9, 10, 11, 12, 15, 18, and 24 years. Data on sex, race/ethnicity, paternal social class, childhood emotional and behavioral problems, and cumulative scores of sleep problems, average calorie intake, physical activity, smoking, and alcohol and substance use in childhood and adolescence were examined as potential confounders. Main Outcomes and Measures: Psychosis risk (definite psychotic experiences, psychotic disorder, at-risk mental state status, and negative symptom score) depression risk (measured using the computerized Clinical Interview Schedule-Revised) were assessed at 24 years. Results: From data available on 5790 participants (3132 [54.1%] female) for FI levels and data available on 10 463 participants (5336 [51.0%] female) for BMI, 3 distinct trajectories for FI levels and 5 distinct trajectories for BMI were noted, all of which were differentiated by mid-childhood. The persistently high FI level trajectory was associated with a psychosis at-risk mental state (adjusted odds ratio [aOR], 5.01; 95% CI, 1.76-13.19) and psychotic disorder (aOR, 3.22; 95% CI, 1.29-8.02) but not depression (aOR, 1.38; 95% CI, 0.75-2.54). A puberty-onset major increase in BMI was associated with depression (aOR, 4.46; 95% CI, 2.38-9.87) but not psychosis (aOR, 1.98; 95% CI, 0.56-7.79). Conclusions and Relevance: The cardiometabolic comorbidity of psychosis and depression may have distinct, disorder-specific early-life origins. Disrupted insulin sensitivity could be a shared risk factor for comorbid cardiometabolic disorders and psychosis. A puberty-onset major increase in BMI could be a risk factor or risk indicator for adult depression. These markers may represent targets for prevention and treatment of cardiometabolic disorders in individuals with psychosis and depression.

Drug Use in Night Owls May Increase the Risk for Mental Health Problems.

Drugs of abuse are widely known to worsen mental health problems, but this relationship may not be a simple causational one. Whether or not a person is susceptible to the negative effects of drugs of abuse may not only be determined by their addictive properties, but also the users' chronotype, which determines their daily activity patterns. The present study investigates the relationship between chronotype, drug use and mental health problems in a cross-sectional community sample. Participants (n = 209) completed a selection of questionnaires online, including the Munich Chronotype Questionnaire, the Depression Anxiety Stress Scale, the Alcohol Use Disorder Identification Test, the Cannabis Use Disorder Identification Test and the Fagerström Test for Nicotine Dependence. We conducted multiple regression models to determine relationships between participants' chronotype and their reported mental health symptoms and then estimated mediation models to investigate the extent to which their drug consumption accounted for the identified associations. Chronotype was significantly associated with participants' overall mental health (ß = 0.16, p = 0.022) and their anxiety levels (ß = 0.18, p = 0.009) but not with levels of depression or stress. However, both relationships were fully mediated by participants' overall drug consumption. Thus, late chronotypes, so-called "night owls", not only use more drugs but consequently have an increased risk for developing anxiety and deteriorating mental health status. This group may be particularly vulnerable to the negative psychological effects of drugs. Our results point toward the importance of considering chronotype in designing preventative and therapeutic innovations, specifically for anxiety, which at present has been largely neglected.

Associations of early adulthood life transitions with changes in fast food intake: a latent trajectory analysis.

BACKGROUND: Early adulthood is a period of rapid personal development when individuals experience major life transitions (e.g. leaving the parental home, leaving education, beginning employment, cohabitation and parenthood). Changes in social and physical environments associated with these transitions may influence development of health-related behaviours. Consumption of fast food is one behaviour associated with poor diet and long-term health outcomes. In this study we assess how frequency of fast food consumption changes across early adulthood, and how major life transitions are associated with changes in fast food intake. METHODS: Data were collected across four waves of the Project EAT study, from mean age 14.9 (SD = 1.6) to mean age 31.1 (SD = 1.6) years. Participants reporting data at two or more waves were included (n = 2902). Participants reported past week frequency of eating food from a fast food restaurant and responded to questions on living arrangements, education and employment participation, and having children. To assess changes in fast food we developed a latent growth model incorporating an underlying trajectory of fast food intake, five life transitions, and time-invariant covariates. RESULTS: Mean fast food intake followed an underlying quadratic trajectory, increasing through adolescence to a maximum of 1.88 (SE 0.94) times/week and then decreasing again through early adulthood to 0.76 (SE 2.06) times/week at wave 4. Beginning full-time employment and becoming a parent both contributed to increases in fast food intake, each resulting in an average increase in weekly fast food intake of 0.16 (p < 0.01) times/week. Analysis of changes between pairs of waves revealed stronger associations for these two transitions between waves 1-2 (mean age 14.9-19.4 years) than seen in later waves. Leaving the parental home and beginning cohabitation were associated with decreases in fast food intake of - 0.17 (p = 0.004) and - 0.16 (p = 0.007) times/week respectively, while leaving full-time education was not associated with any change. CONCLUSIONS: The transitions of beginning full-time employment and becoming a parent were associated with increases in fast food intake. Public health policy or interventions designed to reduce fast food intake in young adults may benefit from particular focus on populations experiencing these transitions, to ameliorate their impact.

Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort.

BACKGROUND: Low-grade inflammation is associated with depression, but studies of specific symptoms are relatively scarce. Association between inflammatory markers and specific symptoms may provide insights into potential mechanism of inflammation-related depression. Using longitudinal data, we have tested whether childhood serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels are associated with specific depressive symptoms in early adulthood. METHODS: In the ALSPAC birth cohort, serum IL-6 and CRP levels were assessed at age 9 years and 19 depressive symptoms were assessed at age 18 years. We used modified Poisson generalised linear regression with robust error variance to estimate the risk ratio (RR) and 95% confidence interval (95% CI) for each depressive symptom. In addition, we used confirmatory factor analysis to create two continuous latent variables representing somatic/neurovegetative and psychological dimension scores. Structural equation modelling was used to test the associations between IL-6 and these dimension scores. RESULTS: Based on data from 2731 participants, IL-6 was associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances. The adjusted RRs for these symptoms at age 18 years for participants in top, compared with bottom, third of IL-6 at age 9 years were 1.75 (95% CI, 1.13-2.69) for diurnal mood variation, 1.50 (95% CI, 1.11-2.02) for concentration difficulties, 1.31 (95% CI, 1.12-1.54) for fatigue, and 1.24 (95% CI, 1.01-1.52) for sleep disturbances. At dimension level, IL-6 was associated with both somatic/neurovegetative (ß = 0.059, SE = 0.024, P = 0.013) and psychological (ß = 0.056, SE = 0.023, P = 0.016) scores. CONCLUSIONS: Inflammation is associated with specific symptoms of depression. Associations with so-called somatic/neurovegetative symptoms of depression such as fatigue, sleep disturbances and diurnal mood variation indicate that these symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression.

Acceptability of screening for mental health difficulties in primary schools: a survey of UK parents.

BACKGROUND: Many children and young people experiencing mental health difficulties (MHD) do not access care, often due to inadequate identification. Schools have a unique potential to improve early identification; however, evidence is limited regarding the acceptability of school-based identification programmes. This study aimed to examine parents' beliefs about the acceptability of school-wide MHD screening in primary schools. METHODS: We collaborated with experts in school-based mental health to develop a questionnaire to measure parental attitudes toward school-wide MHD screening. The questionnaire contained 13 items relating to acceptability; three open-text boxes for comments on harms, benefits, and screening in general; and four questions that captured demographic information. Parents of children attending four primary schools in Cambridgeshire and Norfolk completed the questionnaire. We calculated counts, percentages, and means for each statement, and analysed responses to open-ended questions using content analysis. RESULTS: Two hundred ninety parents returned the questionnaire across the four schools (61% response rate). In the 260 questionnaires analysed, a total of 254 parents (98%) believed that it is important to identify MHD early in life, and 251 (97%) believed that schools have an important role in promoting pupils' emotional health. The majority of parents (N = 213; 82%) thought that screening would be helpful, although 34 parents (13%) thought that screening would be harmful. Perceived harms of screening included inaccurate identification, stigmatisation, and low availability of follow-up care. There was no clear consensus regarding how to obtain consent or provide feedback of screening results. There were no significant differences in responses according to ethnicity, gender, age, or school. CONCLUSIONS: Results suggest that most parents within the socio-demographic context of our study will accept MHD screening within primary schools, and that school-based screening is viable from the perspective of parents. The comments provided about potential harms as well as suggestions for programme delivery are relevant to inform the development and evaluation of acceptable and sustainable school-based identification models. Implementation and scale-up of such programmes will require further understanding of the perspectives of mental health professionals, school staff, and the general public as well as further evaluation against the established standards for identification programmes.

Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study.

OBJECTIVE: Meta-analyses of cross-sectional studies confirm an increase in circulating inflammatory markers during acute psychosis. Longitudinal studies are scarce but are needed to understand whether elevated inflammatory markers are a cause or consequence of illness. We report a longitudinal study of serum C-reactive protein (CRP) in adolescence and subsequent risk of schizophrenia and related psychoses in adulthood in the Northern Finland Birth Cohort 1986. METHOD: Serum high-sensitivity CRP was measured at age 15/16 years in 6362 participants. ICD-10 diagnoses of schizophrenia and related psychoses were obtained from centralised hospital inpatient and outpatient registers up to age 27 years. Logistic regression calculated odds ratios (ORs) for psychotic outcomes associated with baseline CRP levels analysed as both continuous and categorical variables using American Heart Association criteria. Age, sex, body mass index, maternal education, smoking, and alcohol use were included as potential confounders. RESULTS: By age 27years, 88 cases of non-affective psychosis (1.38%), of which 22 were schizophrenia (0.35%), were identified. Adolescent CRP was associated with subsequent schizophrenia. The adjusted OR for schizophrenia by age 27yearsfor each standard deviation (SD) increase in CRP levels at age 15/16yearswas 1.25 (95% CI, 1.07-1.46), which was consistent with a linear, dose-response relationship (P-value for quadratic term 0.23). Using CRP as a categorical variable, those with high (>3mg/L) compared with low (<1mg/L) CRP levels at baseline were more likely to develop schizophrenia; adjusted OR 4.25 (95% CI, 1.30-13.93). There was some indication that higher CRP was associated with earlier onset of schizophrenia (rs=-0.40; P=0.07). CONCLUSIONS: A longitudinal association between adolescent CRP levels and adult schizophrenia diagnosis indicates a potentially important role of inflammation in the pathogenesis of the illness, although the findings, based on a small number of cases, need to be interpreted with caution and require replication in other samples.

The skinny on cocaine: insights into eating behavior and body weight in cocaine-dependent men.

There is a general assumption that weight loss associated with cocaine use reflects its appetite suppressing properties. We sought to determine whether this was justified by characterizing, in detail, alterations in dietary food intake and body composition in actively using cocaine-dependent individuals. We conducted a cross-sectional case-control comparison of 65 male volunteers from the local community, half of whom satisfied the DSM-IV-TR criteria for cocaine dependence (n=35) while the other half had no personal or family history of a psychiatric disorder, including substance abuse (n=30). Assessments were made of eating behavior and dietary food intake, estimation of body composition, and measurement of plasma leptin. Although cocaine users reported significantly higher levels of dietary fat and carbohydrates as well as patterns of uncontrolled eating, their fat mass was significantly reduced compared with their non-drug using peers. Levels of leptin were associated with fat mass, and with the duration of stimulant use. Tobacco smoking status or concomitant use of medication did not affect the significance of the results. Weight changes in cocaine users reflect fundamental perturbations in fat regulation. These are likely to be overlooked in clinical practice but may produce significant health problems when cocaine use is discontinued during recovery.