Mental illness and cardiovascular health: observational and polygenic score analyses in a population-based cohort study.

BACKGROUND: Individuals with serious mental illness have a markedly shorter life expectancy. A major contributor to premature death is cardiovascular disease (CVD). We investigated associations of (genetic liability for) depressive disorder, bipolar disorder and schizophrenia with a range of CVD traits and examined to what degree these were driven by important confounders. METHODS: We included participants of the Dutch Lifelines cohort (N = 147 337) with information on self-reported lifetime diagnosis of depressive disorder, bipolar disorder, or schizophrenia and CVD traits. Employing linear mixed-effects models, we examined associations between mental illness diagnoses and CVD, correcting for psychotropic medication, demographic and lifestyle factors. In a subsample (N = 73 965), we repeated these analyses using polygenic scores (PGSs) for the three mental illnesses. RESULTS: There was strong evidence that depressive disorder diagnosis is associated with increased arrhythmia and atherosclerosis risk and lower heart rate variability, even after confounder adjustment. Positive associations were also found for the depression PGSs with arrhythmia and atherosclerosis. Bipolar disorder was associated with a higher risk of nearly all CVD traits, though most diminished after adjustment. The bipolar disorder PGSs did not show any associations. While the schizophrenia PGSs was associated with increased arrhythmia risk and lower heart rate variability, schizophrenia diagnosis was not. All mental illness diagnoses were associated with lower blood pressure and a lower risk of hypertension. CONCLUSIONS: Our study shows widespread associations of (genetic liability to) mental illness (primarily depressive disorder) with CVD, even after confounder adjustment. Future research should focus on clarifying potential causal pathways between mental illness and CVD.

Perspectives on scientific error.

Theoretical arguments and empirical investigations indicate that a high proportion of published findings do not replicate and are likely false. The current position paper provides a broad perspective on scientific error, which may lead to replication failures. This broad perspective focuses on reform history and on opportunities for future reform. We organize our perspective along four main themes: institutional reform, methodological reform, statistical reform and publishing reform. For each theme, we illustrate potential errors by narrating the story of a fictional researcher during the research cycle. We discuss future opportunities for reform. The resulting agenda provides a resource to usher in an era that is marked by a research culture that is less error-prone and a scientific publication landscape with fewer spurious findings.

Locus of control is associated with tobacco and alcohol consumption in young adults of the Avon Longitudinal Study of Parents and Children.

Individuals appraise events as a consequence of their own actions (i.e. internal locus of control, LoC) or as the outcome of chance or others' will (i.e. external LoC). We hypothesized that having a more external LoC would be associated with higher risk of tobacco and alcohol use. Few studies have examined this association using large prospective data. We evaluated within the Avon Longitudinal Study of Parents and Children (ALSPAC) the associations between LoC at 16 and tobacco and alcohol consumption at 17 and 21 years using logistic regression. A more external LoC at age 16 (N = 4656) was associated with higher odds of being a weekly smoker at age 17 (OR 1.18, 95% CI 1.10-1.25) and 21 (OR 1.14, 95% CI 1.07-1.21) and with dependence measured using the Fagerström Test of Nicotine Dependence at age 17 (OR 1.26, 95% CI 1.05-1.51) and 21 (OR 1.25, 95% CI 1.05-1.49). Individuals with external LoC at age 16 were more likely to be hazardous drinkers according to the Alcohol Use Disorders Identification Test at age 17 (OR 1.09, 95% CI 1.04-1.15) but not at 21 (OR 1.01, 95% CI 0.96-1.06). Having a more external LoC at age 16 is associated with increased tobacco consumption at age 17 and 21 and alcohol consumption at 17 years. LoC may represent an intervention target for preventing substance use and dependence.

Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man.

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.

Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization.

BACKGROUND: Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one-second (FEV1) and forced vital capacity (FVC). METHODS: We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or ß-estimates with 95% confidence interval (CI). RESULTS: The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: ß=-0.0012 (95% CI: -0.0019, -0.0006) and FVC: ß=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0-24 mL decrease) per 1 kg/m2 higher BMI. CONCLUSIONS: The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.

The Burden of the "False-Negatives" in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures.

The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at phase II. Scenario 2 led, on average, to a 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures.

Variation in the recall of socially rewarding information and depressive symptom severity: a prospective cohort study.

OBJECTIVE: To test the association between recall for socially rewarding (positive) and/or socially critical (negative) information and depressive symptoms. METHOD: Cohort study of people who had visited UK primary care in the past year reporting depressive symptoms (N = 558, 69% female). Positive and negative recall was assessed at three time-points, 2 weeks apart, using a computerised task. Depressive symptoms were assessed at four time-points using the Beck Depression Inventory (BDI). Analyses were conducted using multilevel models. RESULTS: Concurrently we found evidence that, for every increase in two positive words recalled, depressive symptoms reduced by 0.6 (95% CI -1.0 to -0.2) BDI points. This association was not affected by adjustment for confounders. There was no evidence of an association between negative recall and depressive symptoms (-0.1, 95% CI -0.5 to 0.3). Longitudinally, we found more evidence that positive recall was associated with reduced depressive symptoms than vice versa. CONCLUSION: People with more severe depressive symptoms recall less positive information, even if their recall of negative information is unaltered. Clinicians could put more emphasis on encouraging patients to recall positive, socially rewarding information, rather than trying to change negative interpretations of events that have already occurred.

Cognitive bias modification for facial interpretation: a randomized controlled trial of transfer to self-report and cognitive measures in a healthy sample.

Cognitive bias modification is a potential low-intensity intervention for mood disorders, but previous studies have shown mixed success. This study explored whether facial interpretation bias modification (FIBM), a similar paradigm designed to shift emotional interpretation (and/or perception) of faces would transfer to: (i) self-reported symptoms and (ii) a battery of cognitive tasks. In a preregistered, double-blind randomized controlled trial, healthy participants received eight online sessions of FIBM (N = 52) or eight sham sessions (N = 52). While we replicate that FIBM successfully shifts ambiguous facial expression interpretation in the intervention group, this failed to transfer to the majority of self-report or cognitive measures. There was, however, weak, inconclusive evidence of transfer to a self-report measure of stress, a cognitive measure of anhedonia, and evidence that results were moderated by trait anxiety (whereby transference was greatest in those with higher baseline symptoms). We discuss the need for work in both larger and clinical samples, while urging caution that these FIBM training effects may not transfer to clinically relevant domains.

Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study.

BACKGROUND: Observational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data. METHOD: We performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10-5) and schizophrenia (p < 5 × 10-8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses. RESULTS: There was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01-1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05-1.14, p = 2.64 × 10-5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99-1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97-1.00, p = 0.066) analyses. CONCLUSIONS: Our results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

Gamification for health promotion: systematic review of behaviour change techniques in smartphone apps.

OBJECTIVE: Smartphone games that aim to alter health behaviours are common, but there is uncertainty about how to achieve this. We systematically reviewed health apps containing gaming elements analysing their embedded behaviour change techniques. METHODS: Two trained researchers independently coded apps for behaviour change techniques using a standard taxonomy. We explored associations with user ratings and price. DATA SOURCES: We screened the National Health Service (NHS) Health Apps Library and all top-rated medical, health and wellness and health and fitness apps (defined by Apple and Google Play stores based on revenue and downloads). We included free and paid English language apps using 'gamification' (rewards, prizes, avatars, badges, leaderboards, competitions, levelling-up or health-related challenges). We excluded apps targeting health professionals. RESULTS: 64 of 1680 (4%) health apps included gamification and met inclusion criteria; only 3 of these were in the NHS Library. Behaviour change categories used were: feedback and monitoring (n=60, 94% of apps), reward and threat (n=52, 81%), and goals and planning (n=52, 81%). Individual techniques were: self-monitoring of behaviour (n=55, 86%), non-specific reward (n=49, 82%), social support unspecified (n=48, 75%), non-specific incentive (n=49, 82%) and focus on past success (n=47, 73%). Median number of techniques per app was 14 (range: 5-22). Common combinations were: goal setting, self-monitoring, non-specific reward and non-specific incentive (n=35, 55%); goal setting, self-monitoring and focus on past success (n=33, 52%). There was no correlation between number of techniques and user ratings (p=0.07; rs=0.23) or price (p=0.45; rs=0.10). CONCLUSIONS: Few health apps currently employ gamification and there is a wide variation in the use of behaviour change techniques, which may limit potential to improve health outcomes. We found no correlation between user rating (a possible proxy for health benefits) and game content or price. Further research is required to evaluate effective behaviour change techniques and to assess clinical outcomes. TRIAL REGISTRATION NUMBER: CRD42015029841.

Citation bias and selective focus on positive findings in the literature on the serotonin transporter gene (5-HTTLPR), life stress and depression.

BACKGROUND: Caspi et al.'s 2003 report that 5-HTTLPR genotype moderates the influence of life stress on depression has been highly influential but remains contentious. We examined whether the evidence base for the 5-HTTLPR-stress interaction has been distorted by citation bias and a selective focus on positive findings. METHOD: A total of 73 primary studies were coded for study outcomes and focus on positive findings in the abstract. Citation rates were compared between studies with positive and negative results, both within this network of primary studies and in Web of Science. In addition, the impact of focus on citation rates was examined. RESULTS: In all, 24 (33%) studies were coded as positive, but these received 48% of within-network and 68% of Web of Science citations. The 38 (52%) negative studies received 42 and 23% of citations, respectively, while the 11 (15%) unclear studies received 10 and 9%. Of the negative studies, the 16 studies without a positive focus (42%) received 47% of within-network citations and 32% of Web of Science citations, while the 13 (34%) studies with a positive focus received 39 and 51%, respectively, and the nine (24%) studies with a partially positive focus received 14 and 17%. CONCLUSIONS: Negative studies received fewer citations than positive studies. Furthermore, over half of the negative studies had a (partially) positive focus, and Web of Science citation rates were higher for these studies. Thus, discussion of the 5-HTTLPR-stress interaction is more positive than warranted. This study exemplifies how evidence-base-distorting mechanisms undermine the authenticity of research findings.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Are IQ and educational outcomes in teenagers related to their cannabis use? A prospective cohort study.

There is much debate about the impact of adolescent cannabis use on intellectual and educational outcomes. We investigated associations between adolescent cannabis use and IQ and educational attainment in a sample of 2235 teenagers from the Avon Longitudinal Study of Parents and Children. By the age of 15, 24% reported having tried cannabis at least once. A series of nested linear regressions was employed, adjusted hierarchically by pre-exposure ability and potential confounds (e.g. cigarette and alcohol use, childhood mental-health symptoms and behavioural problems), to test the relationships between cumulative cannabis use and IQ at the age of 15 and educational performance at the age of 16. After full adjustment, those who had used cannabis ⩾ 50 times did not differ from never-users on either IQ or educational performance. Adjusting for group differences in cigarette smoking dramatically attenuated the associations between cannabis use and both outcomes, and further analyses demonstrated robust associations between cigarette use and educational outcomes, even with cannabis users excluded. These findings suggest that adolescent cannabis use is not associated with IQ or educational performance once adjustment is made for potential confounds, in particular adolescent cigarette use. Modest cannabis use in teenagers may have less cognitive impact than epidemiological surveys of older cohorts have previously suggested.

Changing mothers' perception of infant emotion: a pilot study.

Cognitive bias modification (CBM) techniques, which experimentally retrain abnormal processing of affective stimuli, are becoming established for various psychiatric disorders. Such techniques have not yet been applied to maternal processing of infant emotion, which is affected by various psychiatric disorders. In a pilot study, mothers of children under 3 years old (n = 2) were recruited and randomly allocated to one of three training exercises, aiming either to increase or decrease their threshold of perceiving distress in a morphed continuum of 15 infant facial images. Differences between pre- and post-training threshold were analysed between and within subjects. Compared to baseline thresholds, the threshold for perceiving infant distress decreased in the lowered threshold group (mean difference -1.7 frames, 95 % confidence intervals (CI) -3.1 to -0.3, p = 0.02), increased in the raised threshold group (1.3 frames, 95 % CI 0.6 to 2.1, p < 0.01) and was unchanged in the control group (0.1 frames, 95 % CI -0.8 to 1.1, p = 0.80). Between-group differences were similarly robust in regression models and were not attenuated by potential confounders. The findings suggest that it is possible to change the threshold at which mothers perceive ambiguous infant faces as distressed, either to increase or decrease sensitivity to distress. This small study was intended to provide proof of concept (i.e. that it is possible to alter a mother's perception of infant distress). Questions remain as to whether the effects persist beyond the immediate experimental session, have an impact on maternal behaviour and could be used in clinical samples to improve maternal sensitivity and child outcomes.

Is there an excess of significant findings in published studies of psychotherapy for depression?

BACKGROUND: Many studies have examined the efficacy of psychotherapy for major depressive disorder (MDD) but publication bias against null results may exist in this literature. However, to date, the presence of an excess of significant findings in this literature has not been explicitly tested. METHOD: We used a database of 1344 articles on the psychological treatment of depression, identified through systematic search in PubMed, PsycINFO, EMBASE and the Cochrane database of randomized trials. From these we identified 149 studies eligible for inclusion that provided 212 comparisons. We tested for an excess of significant findings using the method developed by Ioannidis and Trikalinos (2007), and compared the distribution of p values in this literature with the distribution in the antidepressant literature, where publication bias is known to be operating. RESULTS: The average statistical power to detect the effect size indicated by the meta-analysis was 49%. A total of 123 comparisons (58%) reported a statistically significant difference between treatment and control groups, but on the basis of the average power observed, we would only have expected 104 (i.e. 49%) to do so. There was therefore evidence of an excess of significance in this literature (p = 0.010). Similar results were obtained when these analyses were restricted to studies including a cognitive behavioural therapy (CBT) arm. Finally, the distribution of p values for psychotherapy studies resembled that for published antidepressant studies, where publication bias against null results has already been established. CONCLUSIONS: The small average size of individual psychotherapy studies is only sufficient to detect large effects. Our results indicate an excess of significant findings relative to what would be expected, given the average statistical power of studies of psychotherapy for major depression.

Has analytical flexibility increased in imaging studies of bipolar disorder and major depression?

There has been extensive discussion of problems of reproducibility of research. Analytical flexibility may contribute to this, by increasing the likelihood that a reported finding represents a chance result. We explored whether analytical flexibility has increased over time, using human imaging studies of bipolar disorder and major depression. Our results indicate that the number of measures collected per study has increased over time for studies of bipolar disorder, but not for studies of major depression.