Seasonality of presentation and birth in catatonia.

BACKGROUND: Catatonia is a neuropsychiatric syndrome associated with both psychiatric disorders and medical conditions. Understanding of the pathophysiology of catatonia remains limited, and the role of the environment is unclear. Although seasonal variations have been shown for many of the disorders underlying catatonia, the seasonality of this syndrome has not yet been adequately explored. METHODS: Clinical records were screened to identify a cohort of patients suffering from catatonia and a control group of psychiatric inpatients, from 2007 to 2016 in South London. In a cohort study, the seasonality of presentation was explored fitting regression models with harmonic terms, while the effect of season of birth on subsequent development of catatonia was analyzed using regression models for count data. In a case-control study, the association between month of birth and catatonia was studied fitting logistic regression models. RESULTS: In total, 955 patients suffering from catatonia and 23,409 controls were included. The number of catatonic episodes increased during winter, with a peak in February. Similarly, an increasing number of cases was observed during summer, with a second peak in August. However, no evidence for an association between month of birth and catatonia was found. CONCLUSIONS: The presentation of catatonia showed seasonal variation in accordance with patterns described for many of the disorders underlying catatonia, such as mood disorders and infections. We found no evidence for an association between season of birth and risk of developing catatonia. This may imply that recent triggers may underpin catatonia, rather than distal events.

The association of alcohol dependence and consumption during adolescence with depression in young adulthood, in England: a prospective cohort study.

BACKGROUND: The role of alcohol use in the development of depression is unclear. We aimed to investigate whether alcohol dependence, but not high frequency or quantity of consumption, during adolescence increased the risk of depression in young adulthood. METHODS: In this prospective cohort study, we included adolescents who were born to women recruited to the Avon Longitudinal Study of Parents and Children in Avon, UK, with delivery dates between April 1, 1991, and Dec 31, 1992. Alcohol dependence and consumption were measured at about age 16 years, 18 years, 19 years, 21 years, and 23 years using the self-reported Alcohol Use Disorders Identification Test, and at about age 18 years, 21 years, and 23 years using items corresponding to DSM-IV symptoms. The primary outcome was depression at age 24 years, assessed using the Clinical Interview Schedule Revised. Analyses were probit regressions between growth factors for alcohol dependence and consumption and depression, before and after adjustments for confounders: sex, housing tenure, maternal education, maternal depressive symptoms, parents' alcohol use, conduct problems at age 4 years, being bullied from age 12-16 years, and frequency of smoking cigarettes or cannabis. Adolescents were included in analyses if they had data from at least one timepoint for alcohol use and confounders. FINDINGS: We included 3902 adolescents (2264 [58·0%] female; 1638 [42·0%] male) in our analysis, and 3727 (96·7%) of 3853 participants with data on ethnicity were White. After adjustments, we found a positive association between alcohol dependence at 18 years of age (latent intercept) and depression at 24 years of age (probit coefficient 0·13 [95% CI 0·02 to 0·25]; p=0·019), but no association between rate of change (linear slope) and depression (0·10 [-0·82 to 1·01]; p=0·84). There was no evidence of an association between alcohol consumption and depression (latent intercept probit coefficient -0·01 [-0·06 to 0·03]; p=0·60; linear slope 0·01 [-0·40 to 0·42]; p=0·96) after adjustments. INTERPRETATION: Psychosocial or behavioural interventions that reduce the risk of alcohol dependence during adolescence could contribute to preventing depression in young adulthood. FUNDING: UK Medical Research Council and Alcohol Research UK (grant number MR/L022206/1).

Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology developed an evidence-based consensus guideline on the management of catatonia. A group of international experts from a wide range of disciplines was assembled. Evidence was gathered from existing systematic reviews and the primary literature. Recommendations were made on the basis of this evidence and were graded in terms of their strength. The guideline initially covers the diagnosis, aetiology, clinical features and descriptive epidemiology of catatonia. Clinical assessments, including history, physical examination and investigations are then considered. Treatment with benzodiazepines, electroconvulsive therapy and other pharmacological and neuromodulatory therapies is covered. Special regard is given to periodic catatonia, malignant catatonia, neuroleptic malignant syndrome and antipsychotic-induced catatonia. There is attention to the needs of particular groups, namely children and adolescents, older adults, women in the perinatal period, people with autism spectrum disorder and those with certain medical conditions. Clinical trials were uncommon, and the recommendations in this guideline are mainly informed by small observational studies, case series and case reports, which highlights the need for randomised controlled trials and prospective cohort studies in this area.

Catatonia: demographic, clinical and laboratory associations.

BACKGROUND: Catatonia, a severe neuropsychiatric syndrome, has few studies of sufficient scale to clarify its epidemiology or pathophysiology. We aimed to characterise demographic associations, peripheral inflammatory markers and outcome of catatonia. METHODS: Electronic healthcare records were searched for validated clinical diagnoses of catatonia. In a case-control study, demographics and inflammatory markers were compared in psychiatric inpatients with and without catatonia. In a cohort study, the two groups were compared in terms of their duration of admission and mortality. RESULTS: We identified 1456 patients with catatonia (of whom 25.1% had two or more episodes) and 24 956 psychiatric inpatients without catatonia. Incidence was 10.6 episodes of catatonia per 100 000 person-years. Patients with and without catatonia were similar in sex, younger and more likely to be of Black ethnicity. Serum iron was reduced in patients with catatonia [11.6 v. 14.2 µmol/L, odds ratio (OR) 0.65 (95% confidence interval (CI) 0.45-0.95), p = 0.03] and creatine kinase was raised [2545 v. 459 IU/L, OR 1.53 (95% CI 1.29-1.81), p < 0.001], but there was no difference in C-reactive protein or white cell count. N-Methyl-d-aspartate receptor antibodies were significantly associated with catatonia, but there were small numbers of positive results. Duration of hospitalisation was greater in the catatonia group (median: 43 v. 25 days), but there was no difference in mortality after adjustment. CONCLUSIONS: In the largest clinical study of catatonia, we found catatonia occurred in approximately 1 per 10 000 person-years. Evidence for a proinflammatory state was mixed. Catatonia was associated with prolonged inpatient admission but not with increased mortality.

Clozapine as a treatment for catatonia: A systematic review.

Catatonia is a neuropsychiatric disorder characterised by altered movement, speech, and behaviour. Clozapine is an established therapy for treatment-resistant schizophrenia, but its role in catatonia has not been systematically examined. In this systematic review, we aimed to assess the evidence for clozapine as a treatment for catatonia. Full text original research articles in English where at least one patient with catatonia was treated with clozapine were included, provided catatonia did not occur solely in the context of neuroleptic malignant syndrome. Results were tabulated with calculations of summary statistics presented. Risk of bias was assessed with the Tool for Evaluating the Methodological Quality of Case Reports and Case Series. 182 patients were included, 81 from cohort studies and 101 from case reports or case series. 119/182 patients (65 %) had a specified underlying diagnosis of schizophrenia. Over 80 % of reported patients with catatonia had at least partial remission following treatment with clozapine across both cohort studies and case reports and case series. Among the case reports and series, 24/101 patients (23.8 %) followed clozapine withdrawal. Overall, 25 studies were of low quality, 60 of moderate quality and 8 of high quality. Our findings should be interpreted with caution, as the reliance on case reports, case series and small cohort studies is susceptible to reporting biases, regression to the mean and confounding by other treatments. Future research could use large healthcare databases to ascertain outcomes in those on clozapine with a history of catatonia given the difficulty and expense of conducting randomised controlled trials.

Developing and internally validating a prognostic model (P Risk) to improve the prediction of psychosis in a primary care population using electronic health records: The MAPPED study.

BACKGROUND: An accurate risk prediction algorithm could improve psychosis outcomes by reducing duration of untreated psychosis. OBJECTIVE: To develop and validate a risk prediction model for psychosis, for use by family doctors, using linked electronic health records. METHODS: A prospective prediction study. Records from family practices were used between 1/1/2010 to 31/12/2017 of 300,000 patients who had consulted their family doctor for any nonpsychotic mental health problem. Records were selected from Clinical Practice Research Datalink Gold, a routine database of UK family doctor records linked to Hospital Episode Statistics, a routine database of UK secondary care records. Each patient had 5-8 years of follow up data. Study predictors were consultations, diagnoses and/or prescribed medications, during the study period or historically, for 13 nonpsychotic mental health problems and behaviours, age, gender, number of mental health consultations, social deprivation, geographical location, and ethnicity. The outcome was time to an ICD10 psychosis diagnosis. FINDINGS: 830 diagnoses of psychosis were made. Patients were from 216 family practices; mean age was 45.3 years and 43.5 % were male. Median follow-up was 6.5 years (IQR 5.6, 7.8). Overall 8-year psychosis incidence was 45.8 (95 % CI 42.8, 49.0)/100,000 person years at risk. A risk prediction model including age, sex, ethnicity, social deprivation, consultations for suicidal behaviour, depression/anxiety, substance abuse, history of consultations for suicidal behaviour, smoking history and prescribed medications for depression/anxiety/PTSD/OCD and total number of consultations had good discrimination (Harrell's C = 0.774). Identifying patients aged 17-100 years with predicted risk exceeding 1.0 % over 6 years had sensitivity of 71 % and specificity of 84 %. FUNDING: NIHR, School for Primary Care Research, Biomedical Research Centre.

Clinical Neuroimaging Findings in Catatonia: Neuroradiological Reports of MRI Scans of Psychiatric Inpatients With and Without Catatonia.

OBJECTIVE: Catatonia is a debilitating psychomotor disorder. Previous neuroimaging studies have used small samples with inconsistent results. The authors aimed to describe the structural neuroradiological abnormalities in clinical magnetic resonance imaging (MRI) brain scans of patients with catatonia, comparing them with scans of psychiatric inpatients without catatonia. They report the largest study of catatonia neuroimaging to date. METHODS: In this retrospective case-control study, neuroradiological reports of psychiatric inpatients who had undergone MRI brain scans for clinical reasons were examined. Abnormalities were classified by lateralization, localization, and pathology. The primary analysis was prediction of catatonia by presence of an abnormal MRI scan, adjusted for age, sex, Black race-ethnicity, and psychiatric diagnosis. RESULTS: Scan reports from 79 patients with catatonia and 711 other psychiatric inpatients were obtained. Mean age was 36.4 (SD=17.3) for the cases and 44.5 (SD=19.9) for the comparison group. Radiological abnormalities were reported in 27 of 79 cases (34.2%) and in 338 of 711 in the comparison group (47.5%) (odds ratio [OR]=0.57, 95% confidence interval [CI]=0.35, 0.93; adjusted OR=1.11, 95% CI=0.58, 2.14). Among the cases, most abnormal scans had bilateral abnormalities (N=23, 29.1%) and involved the forebrain (N=25, 31.6%) and atrophy (N=17, 21.5%). CONCLUSIONS: Patients with catatonia were commonly reported to have brain MRI abnormalities, which largely consisted of diffuse cerebral atrophy rather than focal lesions. No evidence was found that these abnormalities were more common than in other psychiatric inpatients undergoing neuroimaging, after adjustment for demographic variables. Study limitations included a heterogeneous control group and selection bias in requesting scans.

Inflammatory and blood gas markers of COVID-19 delirium compared to non-COVID-19 delirium: a cross-sectional study.

OBJECTIVES: We aimed to find the association of inflammation and respiratory failure with delirium in COVID-19 patients. We compare the inflammatory and arterial blood gas markers between patients with COVID-19 delirium and delirium in other medical disorders. METHODS: This cross-sectional study used the CHART-DEL, a validated research tool, to screen patients for delirium retrospectively from clinical notes. Inflammatory markers C-reactive protein (CRP) and white cell count (WBC), and the partial pressures of oxygen (PO2) and carbon dioxide (PCO2) were compared between patients with COVID-19 delirium and delirium in other medical disorders. RESULTS: In bivariate analysis, CRP (mg/L) was significantly higher in the COVID-19 group, (81.7 ± 80.0 vs. 58.8 ± 87.7, p = 0.04), and WBC (109/L) was significantly lower (7.44 ± 3.42 vs. 9.71 ± 5.45, p = 0.04). The geometric mean of CRP in the COVID-19 group was 140% higher in multiple linear regression (95% CI = 7-439%, p = 0.03) with age and sex as covariates. There were no significant differences in pO2 or pCO2 across groups. CONCLUSION: The association between higher CRP and COVID-19 in patients with delirium may suggest an inflammatory basis for delirium in COVID-19. Our findings may assist clinicians in establishing whether delirium is due to COVID-19, which may improve management and outcomes of infected patients.

Longitudinal associations between circulating interleukin-6 and C-reactive protein in childhood, and eating disorders and disordered eating in adolescence.

OBJECTIVE: Few studies have explored the association between inflammation and eating disorders and none used a longitudinal design. We investigated the association between serum-levels of interleukin 6 (IL-6) and C-reactive protein (CRP) measured in childhood and eating disorders and related behaviours and cognitions in adolescence in a large general population sample. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Our exposures were thirds of IL6 and CRP derived from serum measurements taken at age nine years, and outcomes were eating disorder diagnoses and self-reported disordered eating behaviours at ages 14, 16, and 18 years. We used univariable and multivariable multilevel logistic regression models adjusting for a number of potential confounders, including sex, fat mass, and pre-existing mental health difficulties. RESULTS: Our sample included 3480 children. Those in the top third of CRP had lower odds of binge eating (odds ratio(OR):0.62, 95% confidence interval (CI):0.39,1.00,p "equals" 0.05) and fasting (OR:0.63, 95% CI:0.38,1.07,p "equals" 0.09) after adjustment for confounders. We also observed weak associations of comparable magnitude for purging, anorexia nervosa, and bulimia nervosa. We did not find any associations between levels of IL6 and any of the outcomes under study. CONCLUSIONS: There was little evidence of an association between CRP and IL-6 and adolescent eating disorder outcomes. The inverse association observed between CRP and binge eating was unexpected, so caution is needed when interpreting it. One possible explanation is that higher CRP levels could have a protective role for disordered eating by affecting appetitive traits.

Trajectories of internalising and externalising symptoms and inflammation in the general child population.

BACKGROUND: Elevations in inflammatory marker levels have been shown to precede internalising and externalising problems in the general child population. One study has found the reverse, that elevations in inflammatory marker levels in childhood follow internalising and externalising problems. However, the authors did not explore the role of the course of these problems in childhood or adjust for a number of potential confounders including psychosocial stressors and prenatal and perinatal exposures. AIMS: To investigate the association in childhood between the growth of internalising and externalising symptoms and levels of inflammatory markers, while accounting for potential confounders. METHODS: Using data from the Avon Longitudinal Study of Parents and Children, we tested the association between the trajectories of internalising (emotional and social) and externalising (hyperactivity and conduct) problems, at ages 4, 6, 8 and 9 years, and levels of C-reactive protein (CRP) and interleukin 6 (IL-6) at age 9 years. We analysed data (n = 4525) using latent growth curve modelling and linear regression. RESULTS: Children who had increasing levels of internalising symptoms over childhood were more likely to have higher levels of CRP and IL-6 at 9 years of age, even after adjustment for confounders. A one-unit increase in the rate of annual change of internalising symptoms was related to an increase of 12% and 8% in the level of CRP and IL-6, respectively. However, there was no evidence for an association between externalising symptoms and either inflammatory marker. CONCLUSIONS: This study is the first step towards identifying a robust pathway, via increases in emotional and social difficulties, to elevated inflammation in healthy children. This association, if causal, suggests that effective interventions for children experiencing chronic emotional and social difficulties could also have physical health benefits.

Prenatal and childhood adversity and inflammation in children: A population-based longitudinal study.

BACKGROUND: Stressful life events experienced during childhood and early prenatal development have been associated with inflammation during childhood. However, no study has considered these two exposures jointly, or has investigated the effect of their interaction. METHODS: In the Avon Longitudinal Study of Parents and Children, a general-population birth cohort, we explored if inflammatory markers [serum C-reactive protein (CRP) and interleukin 6 (IL-6)] at age 9 years were related to early prenatal events (at 18 weeks pregnancy), childhood events (measured on seven occasions at ages 0-9 years) and their interaction (n = 3,915). Latent growth curve modelling estimated trajectories of childhood events, and linear regression explored associations of prenatal and childhood events with inflammatory markers. Models controlled for ethnicity, socioeconomic status and body mass index, were stratified by gender and considered both unweighted and weighted (by impact) event exposures. RESULTS: Even after adjustment for confounders and prenatal events, both the intercept and the slope of number of childhood events were associated with IL-6, but only in females. The significant effect of the slope held for both weighted (by impact) and unweighted event specifications. Prenatal events were not associated with either inflammatory marker when childhood events were controlled. There was no evidence for synergistic effects of prenatal and childhood events. CONCLUSION: Independently of prenatal adverse life events, the number and increase in number of adverse life events experienced in childhood were associated positively with plasma levels of inflammatory markers, such as IL-6, in girls. This gender specificity warrants further research.

Prenatal and childhood adverse life events, inflammation and depressive symptoms across adolescence.

BACKGROUND: No study has investigated the role of inflammation in explaining the association between early exposures to adverse life events and depressive symptoms in adolescence. METHOD: Using data from the Avon Longitudinal Study of Parents and Children, we tested if inflammatory markers [serum C-reactive protein (CRP) and interleukin 6 (IL-6)] at age 9 years mediate the association between adverse life events, measured separately for the prenatal (since the beginning of pregnancy) and the childhood (ages 0-9 years) periods, and the development of depressive symptoms at ages 10-17 years. Data (n = 4,263) were analyzed using mediation analysis in a latent growth curve modeling framework. RESULTS: Depressive symptoms at the beginning of adolescence (age 10) were associated with the number of prenatal events, the number of events around birth and the increase in events over time in childhood (ages 0-9), even after adjustment for confounders. IL-6 partially mediated the association between increasing exposure to events over time in childhood and depressive symptoms at the beginning of adolescence. IL-6 did not mediate any other association between events and symptoms. There was no evidence for mediation by CRP, which was generally unrelated to exposure to events. LIMITATIONS: The small size of the mediation effect and the robust direct effects of events prenatally and around birth suggest there are multiple routes from early stressors to adolescent depression. CONCLUSIONS: In the general adolescent population, increasing exposure to psychosocial stressors over time during childhood is associated with the early onset of depressive symptoms, partly via increasing levels of plasma IL-6.

Internalising symptoms mediate the longitudinal association between childhood inflammation and psychotic-like experiences in adulthood.

Psychotic-like experiences (PLEs) are part of a continuum of psychosis. Previous longitudinal studies highlighted a relationship between peripheral inflammation during childhood and onset of PLEs in adulthood. In this study, we tested if this association is mediated by internalising and externalising symptoms experienced during childhood and adolescence. To test this hypothesis, we used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We investigated a subsample of 4525 individuals from this cohort with data on interleukin 6 (IL-6) and C-reactive protein (CRP) in childhood (age 9 years). We measured PLEs at age 18 years, and we used latent growth curve modelling to estimate longitudinal trajectories of internalising and externalising symptoms from ages 9 to 16 years. The individual predicted values of the intercept (set at baseline, 9 years) and the slope (rate of annual change) were then used in the mediation analysis. There was evidence for full mediation by the intercept of internalising symptoms. Our findings suggest that inflammation during childhood may be relevant for the future onset of PLEs via its association with a high level of internalising symptoms. These findings, although obtained from a non-clinical population, provide an additional step in advancing knowledge on the relationship between inflammation and symptoms of the psychosis continuum.

Depressive symptoms at age 9-13 and chronic disabling fatigue at age 16: A longitudinal study.

INTRODUCTION: We investigated whether depressive symptoms at ages 9-13 years were associated with chronic disabling fatigue (CDF) at age 16 among children in the Avon Longitudinal Study of Parents & Children (ALSPAC) birth cohort. METHODS: Depressive symptoms at ages 9, 10, 11, 12, and 13 years were defined as a child- or parent-completed Short Mood and Feelings Questionnaire (SMFQ) score ≥11 (range 0-26). SMFQ score was also analysed as a continuous exposure. Chronic disabling fatigue at 16 was defined as fatigue of ≥6 months' but <5 years' duration which prevented school attendance or activities, for which other causes were not identified, and with a Chalder Fatigue Questionnaire score ≥19. Logistic regression was used with multiple imputation to correct for missing data bias. We performed sensitivity analyses in which children who had CDF and depressive symptoms at age 16 were reclassified as not having CDF. RESULTS: In fully adjusted models using imputed data (N = 13,978), depressive symptoms at ages 9, 11, and 13 years were associated with 2- to 3-fold higher odds of CDF at age 16. Each one-point increase in SMFQ score at ages 9, 10, 11, 12, and 13 years was associated with 6-11% higher odds of CDF at age 16. Depressive symptoms and continuous SMFQ scores at each age were not associated with CDF if the outcome was reclassified to exclude children with comorbid depressive symptoms at age 16. CONCLUSIONS: Depressive symptoms at ages 9-13 were associated with chronic disabling fatigue at age 16, but causality is not certain.

Stressful life events, inflammation and emotional and behavioural problems in children: A population-based study.

OBJECTIVE: To test the hypothesis that higher plasma levels of inflammatory markers due to exposure to adverse life events may lead to internalising and externalising symptoms in children. METHOD: Using data from the Avon Longitudinal Study of Parents and Children, a general population birth cohort, we explored if inflammatory markers [serum C-reactive protein (CRP) and interleukin-6 (IL-6)] at age 9 years explain the longitudinal association between adverse life events (at ages 1-9 and 9-11 years) and internalising and externalising symptoms (at ages 9 and 11 years). Data (n = 4583) were analysed using cross-lagged panel modelling to take into account reciprocal associations and reverse causality, and path analyses to test for mediation. Gender, ethnicity, body mass index, maternal education, paternal social class and maternal depression were used as potential confounders. RESULTS: CRP was not associated with adverse life events. There was evidence for partial mediation by IL-6 such that exposure to adverse life events was associated with increased levels of IL-6 later, in turn associated with later internalising symptoms. These associations were robust to adjustment for confounders. IL-6 did not explain part of the opposite association, that of earlier internalising symptoms and later life events, nor did it explain either direction of the association between life events and externalising symptoms. CONCLUSION: Our findings suggest a pathway that may connect early psychosocial adversity and childhood internalising symptoms via higher plasma levels of inflammatory markers, such as IL-6.

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.

Is smoking heaviness causally associated with alcohol use? A Mendelian randomization study in four European cohorts.

Background: Observational studies have shown that tobacco and alcohol use co-occur, but it is not clear whether this relationship is causal. Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank, we used observational methods to test the hypothesis that smoking heaviness increases alcohol consumption. Mendelian randomization (MR) analyses were then used to test the causal relationship between smoking heaviness and alcohol consumption using 55 967 smokers from four European studies [ALSPAC, The Nord-Trøndelag Health Study (HUNT), the Copenhagen General Population Study (CGPS) and UK Biobank]. MR analyses used rs1051730/rs16969968 as a genetic proxy for smoking heaviness. Results: Observational results provided evidence of an association between cigarettes per day and weekly alcohol consumption (increase in units of alcohol per additional cigarette smoked per day = 0.10, 95% confidence interval (CI) 0.05 to 0.15, P ≤ 0.001 in ALSPAC; and 0.48, 95% CI 0.45 to 0.52, P ≤ 0.001 in UK Biobank). However, there was little evidence for an association between rs1051730/rs16969968 and units of alcohol consumed per week across ALSPAC, HUNT, CGPS and UK Biobank (standard deviation increase in units of alcohol per additional copy of the risk allele = -0.004, 95% CI -0.023 to 0.016, P=0.708, I2 = 51.9%). We had 99% and 88% power to detect a change of 0.03 and 0.02 standard deviation units of alcohol per additional copy of the risk allele, respectively. Conclusions: Previously reported associations between smoking and alcohol are unlikely to be causal, and may be the result of confounding and/or reverse causation. This has implications for public health research and intervention research.

Association of Combined Patterns of Tobacco and Cannabis Use in Adolescence With Psychotic Experiences.

Importance: There is concern about potentially causal effects of tobacco use on psychosis, but epidemiological studies have been less robust in attempts to minimize effects of confounding than studies of cannabis use have been. Objectives: To examine the association of patterns of cigarette and cannabis use with preceding and subsequent psychotic experiences, and to compare effects of confounding across these patterns. Design, Setting, and Participants: This cohort study used data from the Avon Longitudinal Study of Parents and Children, which initially consisted of 14 062 children. Data were collected periodically from September 6, 1990, with collection ongoing, and analyzed from August 8, 2016, through June 14, 2017. Cigarette and cannabis use data were summarized using longitudinal latent class analysis to identify longitudinal classes of substance use. Associations between classes and psychotic experiences at age 18 years were assessed. Exposures: Depending on the analysis model, exposures were longitudinal classes of substance use or psychotic experiences at age 12 years. Main Outcomes and Measures: Logistic regression was used to examine the associations between substance use longitudinal classes and subsequent onset of psychotic experiences. Results: Longitudinal classes were derived using 5300 participants (56.1% female) who had at least 3 measures of cigarette and cannabis use from ages 14 to 19 years. Prior to adjusting for a range of potential confounders, there was strong evdience that early-onset cigarette-only use (4.3%), early-onset cannabis use (3.2%), and late-onset cannabis use (11.9%) (but not later-onset cigarette-only use [14.8%]) latent classes were associated with increased psychotic experiences compared with nonusers (65.9%) (omnibus P < .001). After adjusting for confounders, the association for early-onset cigarette-only use attenuated substantially (unadjusted odds ratio [OR], 3.03; 95% CI, 1.13-8.14; adjusted OR, 1.78; 95% CI, 0.54-5.88), whereas those for early-onset cannabis use (adjusted OR, 3.70; 95% CI, 1.66-8.25) and late-onset cannabis use (adjusted OR, 2.97; 95% CI, 1.63-5.40) remained consistent. Conclusions and Relevance: In this study, our findings indicate that while individuals who use cannabis or cigarettes during adolescence have an increased risk of subsequent psychotic experiences, epidemiological evidence is substantively more robust for cannabis use than it is for tobacco use.

Association of Primary Care Consultation Patterns With Early Signs and Symptoms of Psychosis.

Importance: Primary care is an important part of the care pathway for patients with psychosis; therefore, primary care physicians need to be able to accurately identify those at clinical high risk of psychosis. The difficulty of this task is increased because clinical high-risk symptoms are frequently nonspecific to psychosis. Objective: To determine whether the consultation patterns for a prespecified set of symptoms can be used to identify primary care patients who later developed a psychotic illness. Design, Setting, and Participants: This nested case-control study used primary care consultation data collected from 530 primary care practices in 13 UK regions from January 1, 2000, through September 30, 2009. Participants included 11 690 adults with a diagnosis of psychosis and 81 793 control participants who did not have a diagnosis of psychosis individually matched by age group, sex, and primary care practice. Data were analyzed from July 1, 2015, through June 2, 2017. Exposures: Prespecified symptoms selected from literature included attention-deficit/hyperactivity disorder-like symptoms, bizarre behavior, blunted affect, problems associated with cannabis, depressive symptoms, role functioning problems, social isolation, symptoms of mania, obsessive-compulsive disorder-like symptoms, disordered personal hygiene, sleep disturbance, problems associated with cigarette smoking, and suicidal behavior (including self-harm). Main Outcomes and Measures: Case (diagnosis of psychosis) or control (no diagnosis of psychosis) status. Conditional logistic regression was used to investigate the association between symptoms and case-control status in the 5 years before diagnosis. Positive predictive values (PPVs) were calculated using the Bayes theorem for symptoms stratified by age group and sex. Repeated-measures Poisson regression was used to investigate symptom consultation rate. Results: Of the total sample of 93 483 participants, 57.4% were female and 40.0% were older than 60 years (mean [SD] age, 51.34 [21.75] years). Twelve symptoms were associated with a later psychotic diagnosis (all prespecified symptoms except disordered personal hygiene). The strongest association was with suicidal behavior (odds ratio [OR], 19.06; 95% CI, 16.55-21.95). Positive predictive values were heterogeneous across age and sex. The highest PPVs were for suicidal behavior (33.0% in men 24 years or younger [95% CI, 24.2%-43.2%] and 19.6% in women aged 25-34 years [95% CI, 13.7%-27.2%]). Pairs of symptoms were associated with an increase in PPV. Consultation rates were higher in cases and increased 3 months before diagnosis. Conclusions and Relevance: Most of the preselected nonspecific symptoms were associated with a later psychotic diagnosis, particularly among young men consulting for suicidal behavior, especially if consulting with increasing frequency. These symptoms should alert physicians to patients who may benefit from a further assessment of psychotic symptoms.

Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort.

OBJECTIVE: Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. METHOD: We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. RESULTS: Asp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15-0.94). The variant was associated with increased serum IL-6 levels (P = 5.5 × 10-22) but decreased serum CRP levels (P = 3.5 × 10-5), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20). CONCLUSIONS: The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.