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SummaryBackgroundSleep difficulties might be a contributory causal factor in the occurrence of mental health problems. If this is true, improving sleep should benefit psychological health. We aimed to determine whether treating insomnia leads to a reduction in paranoia and hallucinations.MethodsWe did this single-blind, randomised controlled trial (OASIS) at 26 UK universities. University students with insomnia were randomly assigned (1:1) with simple randomisation to receive digital cognitive behavioural therapy (CBT) for insomnia or usual care, and the research team were masked to the treatment. Online assessments took place at weeks 0, 3, 10 (end of therapy), and 22. The primary outcome measures were for insomnia, paranoia, and hallucinatory experiences. We did intention-to-treat analyses. The trial is registered with the ISRCTN registry, number ISRCTN61272251.FindingsBetween March 5, 2015, and Feb 17, 2016, we randomly assigned 3755 participants to receive digital CBT for insomnia (n=1891) or usual practice (n=1864). Compared with usual practice, the sleep intervention at 10 weeks reduced insomnia (adjusted difference 4·78, 95% CI 4·29 to 5·26, Cohen's d=1·11; p<0·0001), paranoia (−2·22, −2·98 to −1·45, Cohen's d=0·19; p<0·0001), and hallucinations (−1·58, −1·98 to −1·18, Cohen's d=0·24; p<0·0001). Insomnia was a mediator of change in paranoia and hallucinations. No adverse events were reported.InterpretationTo our knowledge, this is the largest randomised controlled trial of a psychological intervention for a mental health problem. It provides strong evidence that insomnia is a causal factor in the occurrence of psychotic experiences and other mental health problems. Whether the results generalise beyond a student population requires testing. The treatment of disrupted sleep might require a higher priority in mental health provision.FundingWellcome Trust.

Hearing loss is associated with poor cognitive performance and incident dementia and may contribute to cognitive decline. Treating hearing loss with hearing aids may ameliorate cognitive decline. The purpose of this study was to test whether use of hearing aids was associated with better cognitive performance, and if this relationship was mediated via social isolation and/or depression. Structural equation modelling of associations between hearing loss, cognitive performance, social isolation, depression and hearing aid use was carried out with a subsample of the UK Biobank data set (n = 164,770) of UK adults aged 40 to 69 years who completed a hearing test. Age, sex, general health and socioeconomic status were controlled for as potential confounders. Hearing aid use was associated with better cognition, independently of social isolation and depression. This finding was consistent with the hypothesis that hearing aids may improve cognitive performance, although if hearing aids do have a positive effect on cognition it is not likely to be via reduction of the adverse effects of hearing loss on social isolation or depression. We suggest that any positive effects of hearing aid use on cognition may be via improvement in audibility or associated increases in self-efficacy. Alternatively, positive associations between hearing aid use and cognition may be accounted for by more cognitively able people seeking and using hearing aids. Further research is required to determine the direction of association, if there is any direct causal relationship between hearing aid use and better cognition, and whether hearing aid use results in reduction in rates of cognitive decline measured longitudinally.

Complex intervention trials should be able to answer both pragmatic and explanatory questions in order to test the theories motivating the intervention and help understand the underlying nature of the clinical problem being tested. Key to this is the estimation of direct effects of treatment and indirect effects acting through intermediate variables which are measured post-randomisation. Using psychological treatment trials as an example of complex interventions, we review statistical methods which crucially evaluate both direct and indirect effects in the presence of hidden confounding between mediator and outcome. We review the historical literature on mediation and moderation of treatment effects. We introduce two methods from within the existing causal inference literature, principal stratification and structural mean models, and demonstrate how these can be applied in a mediation context before discussing approaches and assumptions necessary for attaining identifiability of key parameters of the basic causal model. Assuming that there is modification by baseline covariates of the effect of treatment (i.e. randomisation) on the mediator (i.e. covariate by treatment interactions), but no direct effect on the outcome of these treatment by covariate interactions leads to the use of instrumental variable methods. We describe how moderation can occur through post-randomisation variables, and extend the principal stratification approach to multiple group methods with explanatory models nested within the principal strata. We illustrate the new methodology with motivating examples of randomised trials from the mental health literature.

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SummaryBackgroundA quarter of people with psychotic conditions experience persistent auditory verbal hallucinations, despite treatment. AVATAR therapy (invented by Julian Leff in 2008) is a new approach in which people who hear voices have a dialogue with a digital representation (avatar) of their presumed persecutor, voiced by the therapist so that the avatar responds by becoming less hostile and concedes power over the course of therapy. We aimed to investigate the effect of AVATAR therapy on auditory verbal hallucinations, compared with a supportive counselling control condition.MethodsWe did this single-blind, randomised controlled trial at a single clinical location (South London and Maudsley NHS Trust). Participants were aged 18 to 65 years, had a clinical diagnosis of a schizophrenia spectrum (ICD10 F20–29) or affective disorder (F30–39 with psychotic symptoms), and had enduring auditory verbal hallucinations during the previous 12 months, despite continued treatment. Participants were randomly assigned (1:1) to receive AVATAR therapy or supportive counselling with randomised permuted blocks (block size randomly varying between two and six). Assessments were done at baseline, 12 weeks, and 24 weeks, by research assessors who were masked to therapy allocation. The primary outcome was reduction in auditory verbal hallucinations at 12 weeks, measured by total score on the Psychotic Symptoms Rating Scales Auditory Hallucinations (PSYRATS–AH). Analysis was by intention-to-treat with linear mixed models. The trial was prospectively registered with the ISRCTN registry, number 65314790.FindingsBetween Nov 1, 2013, and Jan 28, 2016, 394 people were referred to the study, of whom 369 were assessed for eligibility. Of these people, 150 were eligible and were randomly assigned to receive either AVATAR therapy (n=75) or supportive counselling (n=75). 124 (83%) met the primary outcome. The reduction in PSYRATS–AH total score at 12 weeks was significantly greater for AVATAR therapy than for supportive counselling (mean difference −3·82 [SE 1·47], 95% CI −6·70 to −0·94; p<0·0093). There was no evidence of any adverse events attributable to either therapy.InterpretationTo our knowledge, this is the first powered, randomised controlled trial of AVATAR therapy. This brief, targeted therapy was more effective after 12 weeks of treatment than was supportive counselling in reducing the severity of persistent auditory verbal hallucinations, with a large effect size. Future multi-centre studies are needed to establish the effectiveness of AVATAR therapy and, if proven effective, we think it should become an option in the psychological treatment of auditory verbal hallucinations.FundingWellcome Trust.

Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.

IMPORTANCE Digital cognitive behavioral therapy (dCBT) is a scalable and effective intervention for treating insomnia. Most people with insomnia, however, seek help because of the daytime consequences of poor sleep, which adversely affects quality of life. OBJECTIVES To investigate the effect of dCBT for insomnia on functional health, psychological well-being, and sleep-related quality of life and to determine whether a reduction in insomnia symptoms was a mediating factor. DESIGN, SETTING, AND PARTICIPANTS This online, 2-arm, parallel-group randomized trial comparing dCBT for insomnia with sleep hygiene education (SHE) evaluated 1711 participants with self-reported symptoms of insomnia. Participants were recruited between December 1, 2015, and December 1, 2016, and dCBT was delivered using web and/or mobile channels plus treatment as usual; SHE comprised a website and a downloadable booklet plus treatment as usual. Online assessments took place at 0 (baseline), 4 (midtreatment), 8 (posttreatment), and 24 (follow-up) weeks. Programs were completed within 12 weeks after inclusion. MAIN OUTCOMES AND MEASURES Primary outcomes were scores on self-reported measures of functional health (Patient-Reported Outcomes Measurement Information System: Global Health Scale; range, 10-50; higher scores indicate better health); psychological well-being (Warwick-Edinburgh Mental Well-being Scale; range, 14-70; higher scores indicate greater well-being); and sleep-related quality of life (Glasgow Sleep Impact Index; range, 1-100; higher scores indicate greater impairment). Secondary outcomes comprised mood, fatigue, sleepiness, cognitive failures, work productivity, and relationship satisfaction. Insomnia was assessed with the Sleep Condition Indicator (range: 0-32; higher scores indicate better sleep). RESULTS Of the 1711 participants included in the intention-to-treat analysis, 1329 (77.7%) were female, mean (SD) age was 48.0 (13.8) years, and 1558 (91.1%) were white. Use of dCBT was associated with a small improvement in functional health compared with SHE (adjusted difference [95% CI] at week 4, 0.90 [0.40-1.40]; week 8, 1.76 [1.24-2.28]; week 24, 1.76 [1.22-2.30]) and psychological well-being (adjusted difference [95% CI] at week 4, 1.04 [0.28-1.80]; week 8, 2.68 [1.89-3.47]; week 24, 2.95 [2.13-3.76]), and with a large improvement in sleep-related quality of life (at week 4, −8.76 [−11.83 to −5.69]; week 8,-17.60 [−20.81 to −14.39]; week 24, −18.72 [−22.04 to −15.41]) (all P < .01). A large improvement in insomnia mediated these outcomes (range mediated, 45.5%-84.0%). CONCLUSIONS AND RELEVANCE Use of dCBT is effective in improving functional health, psychological well-being, and sleep-related quality of life in people reporting insomnia symptoms. A reduction in insomnia symptoms mediates these improvements. These results confirm that dCBT improves both daytime and nighttime aspects of insomnia, strengthening existing recommendations of CBT as the treatment of choice for insomnia.