Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation.

Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, (an archetypal generalized inflammatory marker) and/or IL-6 activity, as a potential explanation for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated reciprocal relationships of lifetime smoking with depression (ORSmk-Dep = 2.01, 95% CI 1.71-2.37, p < 0.001; ORDep-Smk = 1.09, 95% CI 1.06-1.13, p < 0.001), CRP levels and IL-6 activity (ORSmk-CRP = 1.40, 95% CI 1.21-1.55, p < 0.001; ORCRP-Smk = 1.03, 95% CI 1.02-1.05, p < 0.001, ORIL-6/CRP-Smk = 1.06 (1.03-1.09), p < 0.001). These associations were also supported by the majority of the robust MR methods performed. We did not find evidence for a reciprocal relationship between CRP levels (using > 500 genetic instruments for CRP) and depression (ORCRP-Dep = 1.01, 95% CI 0.99-1.04; ORDep-CRP = 1.03, 95% CI 0.99-1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to measures of generalized inflammation, but we found evidence for an attenuation of the smoking-depression association in multivariable mendelian randomization when adjusting for IL-6 activity, suggesting that the IL-6 pathway may be at least in part responsible for the association of smoking and depression. Our study supports potential bidirectional causal associations between lifetime smoking and depression which may be at least in part explained by the IL-6 signalling pathway. The IL-6 pathway may represent a putative therapeutic target for smoking and to mitigate the effects of smoking on depression.

Childhood immuno-metabolic markers and risk of depression and psychosis in adulthood: A prospective birth cohort study.

BACKGROUND: Metabolic and inflammatory disorders commonly co-occur with depression and psychosis, with emerging evidence implicating immuno-metabolic dysfunction in their aetiology. Previous studies have reported metabolic dysfunction and inflammation in adults with depression and psychosis. However, longitudinal studies testing the direction of association, and the effects of different dimensions of early-life immuno-metabolic dysfunction on adult psychopathology are limited. METHODS: Using data from 3258 birth cohort participants we examined longitudinal associations of three metabolic hormones (leptin, adiponectin, insulin) at age 9 with risks for depression- and psychosis-spectrum outcomes at age 24. In addition, using nine immuno-metabolic biomarkers (leptin, adiponectin, insulin, interleukin-6, C-Reactive protein, low density lipoprotein, high density lipoprotein, triglycerides, and BMI), we constructed an exploratory bifactor model showing a general immuno-metabolic factor and three specific factors (adiposity, inflammation, and insulin resistance), which were also used as exposures. RESULTS: Childhood leptin was associated with adult depressive episode (adjusted odds ratio (aOR)= 1.31; 95% CI, 1.02-1.71) and negative symptoms (aOR=1.15; 95% CI, 1.07-1.24), but not positive psychotic symptoms. The general immuno-metabolic factor was associated with atypical depressive symptoms (aOR=1.07; 95% CI, 1.01-1.14) and psychotic experiences (aOR=1.21; 95% CI, 1.02-1.44). The adiposity factor was associated with negative symptoms (aOR=1.07; 95% CI 1.02-1.12). Point estimates tended to be larger in women, though 95% credible intervals overlapped with those for men. In women, the inflammatory factor was associated with depressive episodes (aOR=1.27; 95% CI, 1.03-1.57). CONCLUSIONS: While general immuno-metabolic dysfunction in childhood may contribute to risks for both psychotic and depressive symptoms in adulthood, childhood adiposity and inflammation appear to be particularly linked to affective (depressive and negative), but not positive psychotic symptoms.

Cardiometabolic risk prediction algorithms for young people with psychosis: a systematic review and exploratory analysis.

OBJECTIVE: Cardiometabolic risk prediction algorithms are common in clinical practice. Young people with psychosis are at high risk for developing cardiometabolic disorders. We aimed to examine whether existing cardiometabolic risk prediction algorithms are suitable for young people with psychosis. METHODS: We conducted a systematic review and narrative synthesis of studies reporting the development and validation of cardiometabolic risk prediction algorithms for general or psychiatric populations. Furthermore, we used data from 505 participants with or at risk of psychosis at age 18 years in the ALSPAC birth cohort, to explore the performance of three algorithms (QDiabetes, QRISK3 and PRIMROSE) highlighted as potentially suitable. We repeated analyses after artificially increasing participant age to the mean age of the original algorithm studies to examine the impact of age on predictive performance. RESULTS: We screened 7820 results, including 110 studies. All algorithms were developed in relatively older participants, and most were at high risk of bias. Three studies (QDiabetes, QRISK3 and PRIMROSE) featured psychiatric predictors. Age was more strongly weighted than other risk factors in each algorithm. In our exploratory analysis, calibration plots for all three algorithms implied a consistent systematic underprediction of cardiometabolic risk in the younger sample. After increasing participant age, calibration plots were markedly improved. CONCLUSION: Existing cardiometabolic risk prediction algorithms cannot be recommended for young people with or at risk of psychosis. Existing algorithms may underpredict risk in young people, even in the face of other high-risk features. Recalibration of existing algorithms or a new tailored algorithm for the population is required.

Insulin resistance and obesity, and their association with depression in relatively young people: findings from a large UK birth cohort.

BACKGROUND: Depression frequently co-occurs with disorders of glucose and insulin homeostasis (DGIH) and obesity. Low-grade systemic inflammation and lifestyle factors in childhood may predispose to DGIH, obesity and depression. We aim to investigate the cross-sectional and longitudinal associations among DGIH, obesity and depression, and to examine the effect of demographics, lifestyle factors and antecedent low-grade inflammation on such associations in young people. METHODS: Using the Avon Longitudinal Study of Parents and Children birth cohort, we used regression analyses to examine: (1) cross-sectional and (2) longitudinal associations between measures of DGIH [insulin resistance (IR); impaired glucose tolerance] and body mass index (BMI) at ages 9 and 18 years, and depression (depressive symptoms and depressive episode) at age 18 years and (3) whether sociodemographics, lifestyle factors or inflammation [interleukin-6 (IL-6) at age 9 years] confounded any such associations. RESULTS: We included 3208 participants. At age 18 years, IR and BMI were positively associated with depression. These associations may be explained by sociodemographic and lifestyle factors. There were no longitudinal associations between DGIH/BMI and depression, and adjustment for IL-6 and C-reactive protein did not attenuate associations between IR/BMI and depression; however, the longitudinal analyses may have been underpowered. CONCLUSIONS: Young people with depression show evidence of DGIH and raised BMI, which may be related to sociodemographic and lifestyle effects such as deprivation, smoking, ethnicity and gender. In future, studies with larger samples are required to confirm this. Preventative strategies for the poorer physical health outcomes associated with depression should focus on malleable lifestyle factors.

Problem behaviours and psychotropic medication use in intellectual disability: a multinational cross-sectional survey.

BACKGROUND: Problem behaviours (PBs) are a common cause for clinician contact in people with disorders of intellectual development and may be a common cause for the prescription of psychotropic medication. We aimed to use a large, multinational sample to define the prevalence of PBs, the associations with psychotropic medication use, and to assess for any potential 'diagnostic overshadowing' by the label of PBs in a population of people with disorders of intellectual development. METHOD: A multinational, multi-setting, cross-sectional service evaluation and baseline audit was completed. Data were collected from UK hospitals, UK community settings, Sri Lanka and Hong Kong. A semi-structured questionnaire was completed by treating clinicians, capturing demographic details, prevalence rates of intellectual disability and psychotropic medication use, alongside psychiatric co-morbidity. RESULTS: A sample size of 358 was obtained, with 65% of included participants treated in an inpatient setting. Psychotropic use was prevalent (90%) in our sample, particularly antipsychotics (74%). The prevalence of PB was high (83%). There was no statistically significant association between psychotropic prescription and recorded psychiatric co-morbidity, suggesting prevalent 'off-label' use for PBs, or poor recording of psychiatric co-morbidity. There was some evidence of possible diagnostic overshadowing due to the PB classification. A higher dose of psychotropic medication was associated with aggression toward others (P = 0.03). CONCLUSIONS: We found evidence of prevalent potential 'off-label' use for psychotropic medication, which may be due to PBs. We also found evidence of potential diagnostic-overshadowing, where symptoms of psychiatric co-morbidity may have been attributed to PBs. Our findings provide renewed importance, across borders and health systems, for clinicians to consider a holistic approach to treating PBs, and attempting to best understand the precipitants and predisposing factors before psychotropic prescribing.