Showing papers by "Glyn Lewis published in 2018"

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions

Abstract: GMK is supported by a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (grant no. 80354) and a Gosling Fellowship from the Royal College of Psychiatrists, UK (2015). GMK also received funding support from the Wellcome Trust 094790/Z/10/Z). PBJ acknowledges grant sup port from the Wellcome Trust (095844/Z/11/Z & 088869/Z/09/Z) and NIHR (RP-PG-0606-1335, Cambridge Biomedical Research Centre and CLAHRC East of England). RD has received grants from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (grants R01 NS073939; R01 NS074999).

Marriage and risk of dementia: systematic review and meta-analysis of observational studies

Abstract: Background Being married is associated with healthier lifestyle behaviours and lower mortality and may reduce risk for dementia due to life-course factors. We conducted a systematic review and meta-analysis of studies of the association between marital status and the risk of developing dementia. Methods We searched medical databases and contacted experts in the field for relevant studies reporting the relationship, adjusted for age and sex, between marital status and dementia. We rated methodological quality and conducted random-effects meta-analyses to summarise relative risks of being widowed, divorced or lifelong single, compared with being married. Secondary stratified analyses with meta-regression examined the impact of clinical and social context and study methodology on findings. Results We included 15 studies with 812 047 participants. Compared with those who are married, lifelong single (relative risk=1.42 (95% CI 1.07 to 1.90)) and widowed (1.20 (1.02 to 1.41)) people have elevated risk of dementia. We did not find an association in divorced people. Further analyses showed that less education partially confounds the risk in widowhood and worse physical health the elevated risk in lifelong single people. Compared with studies that used clinical registers for ascertaining dementia diagnoses, those which clinically examined all participants found higher risk for being unmarried. Conclusions Being married is associated with reduced risk of dementia than widowed and lifelong single people, who are also underdiagnosed in routine clinical practice. Dementia prevention in unmarried people should focus on education and physical health and should consider the possible effect of social engagement as a modifiable risk factor.

Course of Cognitive Development From Infancy to Early Adulthood in the Psychosis Spectrum.

Abstract: Importance: Most patients with psychotic disorders experience severe cognitive impairment, but the onset and course of this impairment remain unclear Moreover, the course of cognitive functions in other psychiatric conditions remains largely unexamined Objective To chart the course of general and specific cognitive functions in individuals with psychotic disorders, psychotic experiences, and depression Design, Setting, and Participants The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective cohort study comprising all live births between April 1, 1991, and December 31, 1992, in Avon, England The dates of analysis were September 2015 to July 2016 Participants who underwent cognitive testing at ages 18 months and 4, 8, 15, and 20 years and psychiatric assessment at age 18 years were included Main Outcomes and Measures Individuals with psychotic disorder, psychosis with depression, psychotic experiences, and depression were compared with controls Outcomes were full-scale, verbal, and nonverbal IQ at ages 18 months and 4, 8, 15, and 20 years, as well as measures of processing speed, working memory, language, visuospatial ability, and attention at ages 8 and 20 years Results The following numbers of individuals were available for analyses in this longitudinal birth cohort study: 511 (238 male [466%]) at age 18 months (mean [SD] age, 153 [003] years), 483 (229 male [474%]) at age 4 years (mean [SD] age, 407 [003] years), 3930 (1679 male [427%]) at age 8 years (mean [SD] age, 865 [029] years), 3783 (1686 male [446%]) at age 15 years (mean [SD] age, 1545 [027] years), and 257 (90 male [350%]) at age 20 years (mean [SD] age, 2006 [055] years) Individuals with psychotic disorder showed continually increasing deficits between infancy (18 months) and adulthood (20 years) in full-scale IQ (effect size of change [ESΔ] = −109, P = 02) and nonverbal IQ (ESΔ = −094, P = 008) The depression group showed a small, increasing deficit in nonverbal IQ (ESΔ = −029, P = 04) between infancy and adulthood Between ages 8 and 20 years, the psychotic disorder group exhibited developmental lags (ie, slower growth) in measures of processing speed (ESΔ = −068, P = 001), working memory (ESΔ = −059, P = 004), and attention (ESΔ = −044, P = 001) and large, static deficits in measures of language (ES = −087, P = 005) and visuospatial ability (ES = −090, P = 001) There was only weak evidence for cognitive deficits in the psychosis with depression group and the psychotic experiences group Conclusions and Relevance The findings herein suggest that the origins of psychotic disorder involve dynamic developmental processes, affecting both verbal and nonverbal abilities throughout the first 2 decades of life and leading to increasing dysfunction These developmental processes do not manifest in other psychiatric disorders, such as psychosis with depression and depression

Accuracy of general hospital dementia diagnoses in England: Sensitivity, specificity, and predictors of diagnostic accuracy 2008-2016

Abstract: Introduction Recognizing dementia in general hospitals allows for tailored care. We aimed to assess hospital dementia diagnosis accuracy, changes over time, and predictors of correct identification. Method Retrospective cohort study of people over 65 years, using data from a large mental health care database as gold standard, linked to 2008–2016 English hospital data. Results In 21,387 people who had 138,455 admissions, we found sensitivity and specificity of dementia recording, respectively, to be 78.0% and 92.0% for each person's complete records, and 63.3% and 96.6% for each nonelective admission. Diagnostic sensitivity increased between 2008 and 16. Accurate general hospital recording of the presence of dementia was lower in ethnic minority groups, younger, single people, and those with physical illness. Discussion Dementia diagnosis recording in general hospitals is increasing but remains less likely in some groups. Clinicians should be aware of this inequity and have a higher index of clinical suspicion in these groups.

Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder

Abstract: Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zinc-copper cycles, which regulate metal metabolism, are disrupted in ASD. Using novel tooth-matrix biomarkers that provide direct measures of fetal elemental uptake, we developed a predictive model to distinguish participants who would be diagnosed with ASD in childhood from those who did not develop the disorder. We replicated our findings in three independent studies in the United States and the UK. We show that three quantifiable characteristics of fetal and postnatal zinc-copper rhythmicity are altered in ASD: the average duration of zinc-copper cycles, regularity with which the cycles recur, and the number of complex features within a cycle. In all independent study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in ASD cases. In contrast to controls, in ASD cases, the cycle duration was shorter (F = 52.25, P < 0.001), regularity was reduced (F = 47.99, P < 0.001), and complexity diminished (F = 57.30, P < 0.001). With two distinct classification models that used metal rhythmicity data, we achieved 90% accuracy in classifying cases and controls, with sensitivity to ASD diagnosis ranging from 85 to 100% and specificity ranging from 90 to 100%. These findings suggest that altered zinc-copper rhythmicity precedes the emergence of ASD, and quantitative biochemical measures of metal rhythmicity distinguish ASD cases from controls.

Investigating the genetic architecture of general and specific psychopathology in adolescence

Abstract: Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology. We examine how genetic risk for schizophrenia relates to adolescent psychosis-related and internalizing psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of the developmental pathways at this age. PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine the relationships of these PRSs with psychopathology factors modelled within (i) a correlated factors structure and (ii) a bifactor structure. The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression and anxiety, but, when modelling a general psychopathology factor based on these measures, specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology. Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples.

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

Abstract: 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.

Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR)

Abstract: Objective To investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care. Design Two parallel group multicentre phase III randomised placebo controlled trial. Setting 106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015. Participants 480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up. Main outcome measures Depressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks. Results Beck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug. Conclusion This study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited. Trial registration Current Controlled Trials ISRCTN06653773.

Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation.

Abstract: Introduction Observational studies indicate a potentially causal role for interleukin 6 (IL-6), a proinflammatory cytokine, in pathogenesis of depression, but interventional studies based on patients with depression have not been conducted. Tocilizumab, anti-inflammatory drug, is a humanised monoclonal antibody that inhibits IL-6 signalling and is licensed in the UK for treatment of rheumatoid arthritis. The main objectives of this study are to test whether IL-6 contributes to the pathogenesis of depression and to examine potential mechanisms by which IL-6 affects mood and cognition. A secondary objective is to compare depressed participants with and without evidence of low-grade systemic inflammation. Methods and analysis This is a proof-of-concept, randomised, parallel-group, double-blind, placebo-controlled clinical trial. Approximately 50 participants with International Classification of Diseases 10th revision (ICD-10) diagnosis of depression who have evidence of low-grade inflammation, defined as serum high-sensitivity C reactive protein (hs-CRP) level ≥3 mg/L, will receive either a single intravenous infusion of tocilizumab or normal saline. Blood samples, behavioural and cognitive measures will be collected at baseline and after infusion around day 7, 14 and 28. The primary outcome is somatic symptoms score around day 14 postinfusion. In addition, approximately, 50 depressed participants without low-grade inflammation (serum hs-CRP level Ethics and dissemination The study has been approved by the South Central—Oxford B Research Ethics Committee (REC) (Reference: 18/SC/0118). Study findings will be published in peer-review journals. Findings will be also disseminated by conference/departmental presentations and by social and traditional media. Trial registration number ISRCTN16942542; Pre-results.

The association between pubertal status and depressive symptoms and diagnoses in adolescent females: A population-based cohort study.

Abstract: Background: There is an association between puberty and depression, but many things remain poorly understood. When assessing puberty in females, most studies combine indicators of breast and pubic hair development which are controlled by different hormonal pathways. The contributions of pubertal timing (age at onset) and pubertal status (stage of development, irrespective of timing) are also poorly understood. We tested the hypothesis that stage of breast development in female adolescents, controlled largely by increased estradiol, would be more strongly associated with depression than pubic hair development which occurs in both males and females, and is controlled by adrenal androgens. We investigated whether this association was independent of pubertal timing. Methods: ROOTS is an ongoing cohort of 1,238 adolescents (54% female) recruited in Cambridgeshire (UK) at age 14.5, and followed-up at ages 16 and 17.5. Depression was assessed using the Mood and Feelings Questionnaire (MFQ) and clinical interview. Breast and pubic hair development were assessed at 14.5, using Tanner rating scales. Results: For each increase in Tanner breast stage at 14.5, depressive symptoms increased by 1.4 MFQ points (95% CI 0.6 to 2.3), irrespective of age at onset. Pubic hair status was only associated with depressive symptoms before adjustment for breast status, and was not associated with depression in males. The same pattern was observed longitudinally, and for depression diagnoses. Limitations: We did not directly measure hormone levels, our findings are observational, and the study had a relatively low response rate. Conclusions: Females at more advanced stages of breast development are at increased risk of depression, even if their age at pubertal onset is not early. Alongside social and psychological factors, hormones controlling breast but not pubic hair development may contribute to increased incidence of female depression during puberty.

Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression : the MIR RCT

Abstract: BACKGROUND: Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant. OBJECTIVES: To investigate whether or not combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment-resistant depression (TRD). DESIGN: The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual. SETTING: Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele. PARTICIPANTS: Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression. INTERVENTIONS: Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation. MAIN OUTCOME MEASURES: The primary outcome was depression symptoms at 12 weeks post randomisation compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients' views and experiences of managing depression and GPs' views on prescribing a second antidepressant. RESULTS: There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference -1.83 points, 95% confidence interval (CI) -3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: -0.85 points, 95% CI -3.12 to 1.43 points; 12 months: 0.17 points, 95% CI -2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants). CONCLUSIONS: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant. LIMITATIONS: Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult. FUTURE WORK: Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.

Early adolescent outcomes of joint developmental trajectories of problem behavior and IQ in childhood

Abstract: General cognitive ability (IQ) and problem behavior (externalizing and internalizing problems) are variable and inter-related in children. However, it is unknown how they co-develop in the general child population and how their patterns of co-development may be related to later outcomes. We carried out this study to explore this. Using data from 16,844 Millennium Cohort Study children, we fitted three-parallel-process growth mixture models to identify joint developmental trajectories of internalizing, externalizing and IQ scores at ages 3-11 years. We then examined their associations with age 11 outcomes. We identified a typically developing group (83%) and three atypical groups, all with worse behavior and ability: children with improving behavior and low (but improving in males) ability (6%); children with persistently high levels of problems and low ability (5%); and children with worsening behavior and low ability (6%). Compared to typically developing children, the latter two groups were more likely to show poor decision-making, be bullies or bully victims, engage in antisocial behaviors, skip and dislike school, be unhappy and have low self-esteem. By contrast, children (especially males) in the improver group had outcomes that were similar to, or even better than, those of their typically developing peers. These findings encourage the development of interventions to target children with both cognitive and behavioral difficulties.

Management of treatment-resistant depression in primary care: a mixed-methods study.

Abstract: Background Non-response to antidepressant medication is common in primary care. Little is known about how GPs manage patients with depression that does not respond to medication. Aim To describe usual care for primary care patients with treatment-resistant depression (TRD). Design and setting Mixed-methods study using data from a UK primary care multicentre randomised controlled trial. Method In total, 235 patients with TRD randomised to continue with usual GP care were followed up at 3-month intervals for a year. Self-report data were collected on antidepressant medication, number of GP visits, and other treatments received. In addition, 14 semi-structured face-to-face interviews were conducted with a purposive sample after the 6-month follow-up and analysed thematically. Results Most patients continued on the same dose of a single antidepressant between baseline and 3 months (n = 147/186 at 3 months, 79% (95% confidence interval [CI] = 73 to 85%)). Figures were similar for later follow-ups (for example, 9–12 months: 72% (95% CI = 63 to 79%). Medication changes (increasing dose; switching to a different antidepressant; adding a second antidepressant) were uncommon. Participants described usual care mainly as taking antidepressants, with consultations focused on other (physical) health concerns. Few accessed other treatments or were referred to secondary care. Conclusion Usual care in patients with TRD mainly entailed taking antidepressants, and medication changes were uncommon. The high prevalence of physical and psychological comorbidity means that, when these patients consult, their depression may not be discussed. Strategies are needed to ensure the active management of this large group of patients whose depression does not respond to antidepressant medication.

Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

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

Abstract: 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.

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

Abstract: 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-Trondelag 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.

Effects of exposure to bodies of different sizes on perception of and satisfaction with own body size: two randomized studies.

Abstract: Body dissatisfaction is prevalent among women and associated with subsequent obesity and eating disorders. Exposure to images of bodies of different sizes has been suggested to change the perception of ‘normal’ body size in others. We tested whether exposure to different-sized (otherwise identical) bodies changes perception of own and others9 body size, satisfaction with body size and amount of chocolate consumed. In Study 1, 90 18–25-year-old women with normal BMI were randomized into one of three groups to complete a 15 min two-back task using photographs of women either of ‘normal weight’ (Body Mass Index (BMI) 22–23 kg m −2 ), or altered to appear either under- or over-weight. Study 2 was identical except the 96 participants had high baseline body dissatisfaction and were followed up after 24 h. We also conducted a mega-analysis combining both studies. Participants rated size of others9 bodies, own size, and satisfaction with size pre- and post-task. Post-task ratings were compared between groups, adjusting for pre-task ratings. Participants exposed to over- or normal-weight images subsequently perceived others9 bodies as smaller, in comparison to those shown underweight bodies ( p p = 0.073; Study 2, p = 0.018; mega-analysis, p = 0.001), and felt more satisfied with their size (Study 1, p = 0.046; Study 2, p = 0.004; mega-analysis, p = 0.006). There were no differences in chocolate consumption. This study suggests that a move towards using images of women with a BMI in the healthy range in the media may help to reduce body dissatisfaction, and the associated risk of eating disorders.

Do disordered eating behaviours in girls vary by school characteristics? A UK cohort study

Abstract: Previous research on eating disorders, disordered eating behaviours, and whether their prevalence varies across schools, has produced inconsistent results. Our previous work using Swedish record-linkage data found that rates of diagnosed eating disorders vary between schools, with higher proportions of girls and higher proportions of highly educated parents within a school being associated with greater numbers of diagnosed eating disorders. We aimed to extend these findings to a UK population-based sample and hypothesised that a similar association would be evident when studying disordered eating behaviours. We used data from the Avon Longitudinal Study of Parents and Children to test the hypothesis that prevalence of self- and parent-reported disordered eating behaviours (binge eating, purging, fasting, restrictive eating, and fear of weight gain), and body dissatisfaction cluster by school. We had complete data on body dissatisfaction, school attended, and other possible risk factors for 2146 girls in 263 schools at age 14 and on disordered eating behaviours for 1769 girls in 273 schools at age 16. We used multilevel logistic regression modelling to assess whether prevalence varied between and within schools, and logistic regression to investigate the association between specific school characteristics and prevalence of disordered eating behaviours and body dissatisfaction. At age 14, there was no evidence for body dissatisfaction clustering by school, or for specific school characteristics being associated with body dissatisfaction. At age 16, there was no evidence for clustering, but higher rates of disordered eating behaviours were associated with attending all-girl schools and lower levels with attending schools with higher academic results. We found no evidence for clustering of disordered eating behaviours in individual schools, possibly because of the small cluster sizes. However, we found evidence for higher levels of disordered eating behaviours in 16 years in all-girl schools, and in schools with lower academic performance.

Genetic variation in the Major Histocompatibility Complex and association with depression

Abstract: Background: The prevalence of depression is higher in individuals suffering from autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Epidemiological findings point to a bi-directional relationship - that depression increases the risk of developing an autoimmune disease, and vice-versa. Shared genetic etiology is a plausible explanation for the overlap between depression and autoimmune diseases. In this study we tested whether genetic variation in the Major Histocompatibility Complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Method: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). In the 26 PGC-MDD studies, cases met a lifetime diagnosis of MDD, determined by a structured diagnostic interview. In the UKB, cases and controls were identified from an online mental health questionnaire. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants in each study and performed an inverse-variance weighted meta-analysis across the PGC-MDD and UKB samples, applying both a conservative region-wide significance threshold (3.9-e6) and a candidate threshold (1.6e-4). Results: No HLA alleles or C4 haplotypes were associated with depression at the conservative threshold in the PGC, UKB or meta-analysis. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold in the meta-analysis. Under the conservative threshold, 70 SNPs were detected in the UKB and 143 SNPs were detected in the meta-analysis, mirroring previous findings from highly powered GWAS of depression. Discussion: We found no evidence that HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia, confer risk for depression. These results indicate that autoimmune diseases and depression do not share common risk loci of moderate or large effect in the MHC.

The association between paternal depressogenic cognitive styles during pregnancy and offspring depressogenic cognitive styles: an 18-year prospective cohort study

Abstract: BACKGROUND: Preventing the development of depressogenic or negative cognitive styles could also prevent the development of depression, a leading public health problem worldwide. Maternal negative cognitive styles are a modifiable risk factor for the development of negative cognitive styles in offspring. However, evidence on the role of paternal negative cognitive styles is inconclusive and there have only been a few small studies, which may also have lacked statistical power. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate the association between paternal negative cognitive styles, measured when mothers were 18 weeks pregnant, and offspring negative cognitive styles 18 years later (N = 6,123). Associations were calculated using linear regression models, before and after adjustment for confounders including maternal negative cognitive styles. We compared associations before and after controlling for depression in parents and offspring, and used multiple imputation to reduce biases that may have arisen due to missing data. RESULTS: A two-standard deviation increase in paternal negative cognitive style was associated with a 3-point increase in offspring negative cognitive style (95% CI 1.36-4.37). This association remained after adjustment for confounders and was independent of depression in both parents and offspring. The effect size was equivalent to that of maternal negative cognitive style, and was also independent of maternal negative cognitive style. CONCLUSIONS: Our results suggest that fathers should be included in individual- and family-based interventions designed to prevent the development of depressogenic cognitive styles in adolescent offspring. This could possibly also prevent the development of depression.

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: meta-analysis of data from genome-wide association studies

Abstract: Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was percentage symptom improvement and remission. Side effect data were available at weeks 2-4, 6 and 9 in three of the investigated samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD=0.43, CI=0.19-0.66) and higher remission rates (OR=1.55, CI=1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR=1.26, CI=1.08-1.47), neurological (OR=1.28, CI=1.07-1.53) and sexual side effects (OR=1.52, CI=1.23-1.87; week 6 values similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs are relatively rare among Caucasians (~2%).