Novel and emerging treatments for major depression.

Depression is common, costly, debilitating, and associated with increased risk of suicide. It is one of the leading global public health problems. Although existing available pharmacological treatments can be effective, their onset of action can take up to 6 weeks, side-effects are common, and recovery can require treatment with multiple different agents. Although psychosocial interventions might also be recommended, more effective treatments than those currently available are needed for people with moderate or severe depression. In the past 10 years, treatment trials have developed and tested many new targeted interventions. In this Review, we assess novel and emerging biological treatments for major depressive disorder, evaluate their putative brain and body mechanisms, and highlight how close each might be to clinical use.

Shorter night-time sleep duration and later sleep timing from infancy to adolescence.

BACKGROUND: Here, we (a) examined the trajectories of night-time sleep duration, bedtime and midpoint of night-time sleep (MPS) from infancy to adolescence, and (b) explored perinatal risk factors for persistent poor sleep health. METHODS: This study used data from 12,962 participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Parent or self-reported night-time sleep duration, bedtime and wake-up time were collected from questionnaires at 6, 18 and 30 months, and at 3.5, 4-5, 5-6, 6-7, 9, 11 and 15-16 years. Child's sex, birth weight, gestational age, health and temperament, together with mother's family adversity index (FAI), age at birth, prenatal socioeconomic status and postnatal anxiety and depression, were included as risk factors for persistent poor sleep health. Latent class growth analyses were applied first to detect trajectories of night-time sleep duration, bedtime and MPS, and we then applied logistic regressions for the longitudinal associations between risk factors and persistent poor sleep health domains. RESULTS: We obtained four trajectories for each of the three sleep domains. In particular, we identified a trajectory characterized by persistent shorter sleep, a trajectory of persistent later bedtime and a trajectory of persistent later MPS. Two risk factors were associated with the three poor sleep health domains: higher FAI with increased risk of persistent shorter sleep (OR = 1.20, 95% CI = 1.11-1.30, p < .001), persistent later bedtime (OR = 1.28, 95% CI = 1.19-1.39, p < .001) and persistent later MPS (OR = 1.30, 95% CI = 1.22-1.38, p < .001); and higher maternal socioeconomic status with reduced risk of persistent shorter sleep (OR = 0.99, 95% CI = 0.98-1.00, p = .048), persistent later bedtime (OR = 0.98, 95% CI = 0.97-0.99, p < .001) and persistent later MPS (OR = 0.99, 95% CI = 0.98-0.99, p < .001). CONCLUSIONS: We detected trajectories of persistent poor sleep health (i.e. shorter sleep duration, later bedtime and later MPS) from infancy to adolescence, and specific perinatal risk factors linked to persistent poor sleep health domains.

Impact of anxiety and depression across childhood and adolescence on adverse outcomes in young adulthood: a UK birth cohort study.

BACKGROUND: Little is still known about the long-term impact of childhood and adolescent persistent depression and anxiety in adulthood. AIMS: To investigate the impact of persistent anxiety, depression, and comorbid anxiety and depression across childhood and adolescence on the development of multiple adverse outcomes in young adulthood. METHOD: This study used data from 8122 participants in the Avon Longitudinal Study of Parents and Children cohort. The Development and Well-Being Assessment (DAWBA) examined child anxiety and depression symptomatology. The DAWBA generalised anxiety and mood subscales at 8, 10 and 13 years were selected, and a measure of comorbid anxiety and depression symptoms was created at each time point. Further, several mental and physical health, substance misuse and education/employment problems were assessed at 24 years. Latent class growth analyses were used to detect trajectories of anxiety, depression and comorbid anxiety and depression; and logistic regression to examine how persistent anxiety, depression or both were associated with adverse outcomes at 24 years. RESULTS: All three classes with persistent anxiety, depression or both were significantly associated with presenting with any mental health problems and any education/employment problem. Persistent high levels of depression and high levels of comorbid anxiety and depression, but not persistent high anxiety, were significantly associated with any physical health problem. High levels of comorbid anxiety and depression was the only DAWBA domain significantly associated with substance misuse; and overall, this was the domain that exerted the greatest negative impact, as it presented the highest odd ratio values. CONCLUSIONS: Children and adolescents with comorbid anxiety and depression are at the highest risk for having more adverse outcomes at 24 years.

The effectiveness of a primary care-based collaborative care model to improve quality of life in people with severe mental illness: PARTNERS2 cluster randomised controlled trial.

BACKGROUND: Individuals living with severe mental illness can have significant emotional, physical and social challenges. Collaborative care combines clinical and organisational components. AIMS: We tested whether a primary care-based collaborative care model (PARTNERS) would improve quality of life for people with diagnoses of schizophrenia, bipolar disorder or other psychoses, compared with usual care. METHOD: We conducted a general practice-based, cluster randomised controlled superiority trial. Practices were recruited from four English regions and allocated (1:1) to intervention or control. Individuals receiving limited input in secondary care or who were under primary care only were eligible. The 12-month PARTNERS intervention incorporated person-centred coaching support and liaison work. The primary outcome was quality of life as measured by the Manchester Short Assessment of Quality of Life (MANSA). RESULTS: We allocated 39 general practices, with 198 participants, to the PARTNERS intervention (20 practices, 116 participants) or control (19 practices, 82 participants). Primary outcome data were available for 99 (85.3%) intervention and 71 (86.6%) control participants. Mean change in overall MANSA score did not differ between the groups (intervention: 0.25, s.d. 0.73; control: 0.21, s.d. 0.86; estimated fully adjusted between-group difference 0.03, 95% CI -0.25 to 0.31; P = 0.819). Acute mental health episodes (safety outcome) included three crises in the intervention group and four in the control group. CONCLUSIONS: There was no evidence of a difference in quality of life, as measured with the MANSA, between those receiving the PARTNERS intervention and usual care. Shifting care to primary care was not associated with increased adverse outcomes.

Associations between primary care recorded cannabis use and mental ill health in the UK: a population-based retrospective cohort study using UK primary care data.

BACKGROUND: Cannabis use is a global public health issue associated with increased risks of developing mental health disorders, especially in young people. We aimed to investigate the relationships between cannabis exposure and risks of receiving mental illness diagnoses or treatment as outcomes. METHODS: A population based, retrospective, open cohort study using patients recorded in 'IQVIA medical research data', a UK primary care database. Read codes were used to confirm patients with recorded exposure to cannabis use who were matched up to two unexposed patients. We examined the risk of developing three categories of mental ill health: depression, anxiety or serious mental illness (SMI). RESULTS: At study entry, the exposed cohort had an increased likelihood of having experienced mental ill health [odds ratio (OR) 4.13; 95% confidence interval (CI) 3.99-4.27] and mental ill health-related prescription (OR 2.95; 95% CI 2.86-3.05) compared to the unexposed group. During the study period we found that exposure to cannabis was associated with an increased risk of developing any mental disorder [adjusted hazard ratio (aHR) 2.73; 95% CI 2.59-2.88], also noted when examining by subtype of disorder: anxiety (aHR 2.46; 95% CI 2.29-2.64), depression (aHR 2.34; 95% CI 2.20-2.49) and SMI (aHR 6.41; 95% CI 5.42-7.57). These results remained robust in sensitivity analyses. CONCLUSION: These findings point to the potential need for a public health approach to the management of people misusing cannabis. However, there is a gross under-recording of cannabis use in GP records, as seen by the prevalence of recorded cannabis exposure substantially lower than self-reported survey records.

The role of inflammation in the prospective associations between early childhood sleep problems and ADHD at 10 years: findings from a UK birth cohort study.

BACKGROUND: Several underlying mechanisms potentially account for the link between sleep and attention deficit and hyperactivity disorder (ADHD), including inflammation. However, studies so far have been cross sectional. We investigate (a) the association between early childhood sleep and probable ADHD diagnosis in childhood and (b) whether childhood circulating inflammatory markers mediate these prospective associations. METHODS: Data from the Avon Longitudinal Study of Parents and Children were available for 7,658 10-year-old children. Parent-reported sleep duration, night awakening frequency and regular sleep routines were collected at 3.5 years. The Development and Wellbeing Assessment was administered to capture children with clinically relevant ADHD symptoms, or probable ADHD diagnosis. Blood samples were collected at 9 years, from which two inflammatory markers were obtained [interleukin-6 (IL-6) and C-reactive protein (CRP)]. Logistic regression analyses were applied to investigate the associations between sleep variables at 3.5 years and probable ADHD diagnosis at 10 years. Further, path analysis was applied to examine the potential mediating role of inflammation at 9 years (as measured by CRP and IL-6) in the associations between early sleep and ADHD at 10 years. RESULTS: Less regular sleep routines (OR = 0.51, 95% CI = 0.28-0.93, p = .029), shorter nighttime sleep (OR = 0.70, 95% CI = 0.56-0.89, p = .004) and higher night awakening frequency (OR = 1.27, 95% CI = 1.06-1.52, p = .009) at 3.5 years were associated with higher odds of ADHD at 10 years. Further, IL-6 at 9 years, but not CRP, mediated the association between irregular sleep routines and ADHD (bias-corrected estimate, -0.002; p = .005) and between night awakening and ADHD (bias-corrected estimate, 0.002; p = .003). CONCLUSIONS: Several sleep problems in early childhood constitute a risk factor for probable ADHD diagnosis at 10 years. Further, these associations are partially mediated by IL-6 at 9 years. These results open a new research vista to the pathophysiology of ADHD and highlight sleep and inflammation as potential preventative targets for ADHD.

Cognitive Remediation in Bipolar (CRiB2): study protocol for a randomised controlled trial assessing efficacy and mechanisms of cognitive remediation therapy compared to treatment as usual.

BACKGROUND: A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects. METHODS: CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30-40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models. DISCUSSION: This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action. TRIAL REGISTRATION: Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331 . Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting.

Maternal postnatal depression and anxiety and the risk for mental health disorders in adolescent offspring: Findings from the Avon Longitudinal Study of Parents and Children cohort.

OBJECTIVE: The impacts of postnatal psychiatric disorders on different types of mental health problems in offspring are unclear. We investigated the prospective associations of maternal postnatal depression, and anxiety, with offspring depression, anxiety, psychotic-like experiences and Borderline Personality Disorder symptoms, in adolescence, and examined whether these were independent of each other. METHODS: Data were obtained from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Maternal postnatal depression and anxiety at 8 weeks were measured using the Edinburgh Postnatal Depression Scale and Crown-Crisp Index, respectively. Offspring mental health outcomes were measured at 10-13 years old, using a variety of questionnaire-based and interview assessments. Logistic regression analyses were used to assess the associations between maternal postnatal risk factors and offspring mental health, and path analysis was used to investigate the pathways of maternal postnatal factors to adolescent offspring outcomes. RESULTS: Data were available for 14,054 mothers with information reported on postnatal depression and 13,892 on postnatal anxiety. Logistic regression analyses found significant associations between maternal postnatal depression and offspring anxiety at 10 years old (odds ratio = 1.039, 95% confidence interval = [1.005, 1.073], p = 0.022) and between maternal postnatal anxiety and offspring psychotic experiences at 12/13 years old (odds ratio = 1.042, 95% confidence interval = [1.008, 1.077], p = 0.016). These significant associations remained after applying path analyses, when we controlled for potential offspring psychopathological overlay. CONCLUSION: These findings suggest that mothers with postnatal depression are more likely to have offspring with anxiety at 10 years old, and that mothers with postnatal anxiety are more likely to have offspring with psychotic experiences at 12/13 years old. Our findings suggest specific pathways in the association between postnatal anxiety/depression and offspring mental health and contribute to the importance of identifying mothers and their offspring with increased vulnerability to adverse outcomes resulting from postnatal mental health disorders.

Using intervention mapping to develop evidence-based toolkits that support workers on long-term sick leave and their managers.

BACKGROUND: Managing long-term sickness absence is challenging in countries where employers and managers have the main responsibility to provide return to work support, particularly for workers with poor mental health. Whilst long-term sick leave and return to work frameworks and guidance exist for employers, there are currently no structured return to work protocols for employers or for their workers encompassing best practice strategies to support a positive and timely return to work outcome. PURPOSE: To utilise the intervention mapping (IM) protocol as a framework to develop return to work toolkits that are underpinned by relevant behaviour change theory targeting mental health to promote a positive return to work experiensce for workers on long-term sick leave. METHODS: This paper provides a worked example of intervention mapping (IM) to develop an intervention through a six-step process to combine theory and evidence in the development of two toolkits - one designed for managers and one to be used by workers on long-term sick leave. As part of this process, collaborative planning techniques were used to develop the intervention. A planning group was set up, through which researchers would work alongside employer, worker, and mental health professional representatives to develop the toolkits. Additionally, feedback on the toolkits were sought from the target populations of workers and managers and from wider employer stakeholders (e.g., human resource specialists). The implementation and evaluation of the toolkits as a workplace intervention were also planned. RESULTS: Two toolkits were designed following the six steps of intervention mapping. Feedback from the planning group (n = 5; psychologist, psychiatrist, person with previous experience of poor mental health, employer and charity worker) and participants (n = 14; employers = 3, wellbeing director = 1; human resources = 2, managers = 2, employees with previous experience of poor mental health = 5) target populations indicated that the toolkits were acceptable and much needed. CONCLUSIONS: Using IM allowed the development of an evidence-based practical intervention, whilst incorporating the views of all the impacted stakeholder groups. The feasibility and acceptability of the toolkits and their supporting intervention components, implementation process and methods of assessment will be evaluated in a feasibility pilot randomised controlled trial.

Understanding the development of bipolar disorder and borderline personality disorder in young people: a meta-review of systematic reviews.

BACKGROUND: There is ongoing debate on the nosological position of bipolar disorder (BD) and borderline personality disorder (BPD). Identifying the unique and shared risks, developmental pathways, and symptoms in emerging BD and BPD could help the field refine aetiological hypotheses and improve the prediction of the onset of these disorders. This study aimed to: (a) systematically synthesise the available evidence from systematic reviews (SRs) and meta-analyses (MAs) concerning environmental, psychosocial, biological, and clinical factors leading to the emergence of BD and BPD; (b) identify the main differences and common features between the two disorders to characterise their complex interplay and, (c) highlight remaining evidence gaps. METHODS: Data sources were; PubMed, PsychINFO, Embase, Cochrane, CINAHL, Medline, ISI Web of Science. Overlap of included SRs/MAs was assessed using the corrected covered area process. The methodological quality of each included SR and MA was assessed using the AMSTAR. RESULTS: 22 SRs and MAs involving 249 prospective studies met eligibility criteria. Results demonstrated that family history of psychopathology, affective instability, attention deficit hyperactivity disorder, anxiety disorders, depression, sleep disturbances, substance abuse, psychotic symptoms, suicidality, childhood adversity and temperament were common predisposing factors across both disorders. There are also distinct factors specific to emerging BD or BPD. CONCLUSIONS: Prospective studies are required to increase our understanding of the development of BD and BPD onset and their complex interplay by concurrently examining multiple measures in BD and BPD at-risk populations.

The impact of manic symptoms in first-episode psychosis: Findings from the UK National EDEN study.

OBJECTIVE: The extant literature is inconsistent over whether manic symptoms in first-episode psychosis (FEP) impact on its development and trajectory. This study addressed the following: (1) Does Duration of Untreated Illness (DUI) and Duration of Untreated Psychosis (DUP) differ between FEP patients with and without manic symptoms? (2) Do manic symptoms in FEP have an impact on time to remission over 1 year? METHODS: We used data from the National EDEN study, a longitudinal cohort of patients with FEP accessing early intervention services (EIS) in England, which measured manic, positive and negative psychotic symptoms, depression and functioning at service entry and 1 year. Data from 913 patients with FEP (639 without manic symptoms, 237 with manic symptoms) were analysed using both general linear modelling and survival analysis. RESULTS: Compared to FEP patients without manic symptoms, those with manic symptoms had a significantly longer DUI, though no difference in DUP. At baseline, people with manic symptoms had higher levels of positive and negative psychotic symptoms, depression and worse functioning. At 12 months, people with manic symptoms had significantly poorer functioning and more positive psychotic symptoms. The presence of manic symptoms delayed time to remission over 1 year. There was a 19% reduced rate of remission for people with manic symptoms compared to those without. CONCLUSIONS: Manic symptoms in FEP are associated with delays to treatment. This poorer trajectory persists over 1 year. They appear to be a vulnerable and under-recognised group for poor outcome and need more focussed early intervention treatment.

Vocational rehabilitation via social firms: a qualitative investigation of the views and experiences of employees with mental health problems, social firm managers and clinicians.

BACKGROUND: Employment within social firms in the UK is under-developed and under-researched, but a potentially beneficial route to vocational rehabilitation for people with mental health problems. This study explores the views and experiences of employees with mental ill-health, managers of social firms and mental health clinicians, in order to understand the potential value of social firms for the vocational rehabilitation, employment and well-being of people with mental health problems. METHODS: Semi-structured interviews were conducted with 23 employees with mental health problems in 11 social firms in England. A focus group and individual interviews were conducted with 12 managers of social firms. Two focus groups were held with 16 mental health clinicians. Data were analysed using thematic analysis. RESULTS: Most employees expressed very positive views about working in a social firm. In responses from both employees and social firm managers, an overarching theme regarding the supportive ethos of social firms encompassed several related features: openness about mental health issues; peer, team and management support; flexibility; and support to progress and develop skills over time. Managers identified benefits of employing people with mental health problems who were sufficiently recovered. Knowledge of social firms within clinician focus groups was very limited, although clinicians thought they could be a welcome additional vocational resource. CONCLUSIONS: High levels of job satisfaction among social firm employees may be explained by the supportive ethos of these working environments. Social firms have potential to be a helpful addition to the range of vocational pathways available for people with mental ill-health. Further mixed methods investigations of experiences and outcomes in order to understand who engages with and benefits from this form of vocational rehabilitation would be valuable in informing decisions about scaling up the model.

The prevalence of personality disorders in the community: a global systematic review and meta-analysis.

BACKGROUND: Personality disorders are now internationally recognised as a mental health priority. Nevertheless, there are no systematic reviews examining the global prevalence of personality disorders. AIMS: To calculate the worldwide prevalence of personality disorders and examine whether rates vary between high-income countries and low- and middle-income countries (LMICs). METHOD: We systematically searched PsycINFO, MEDLINE, EMBASE and PubMed from January 1980 to May 2018 to identify articles reporting personality disorder prevalence rates in community populations (PROSPERO registration number: CRD42017065094). RESULTS: A total of 46 studies (from 21 different countries spanning 6 continents) satisfied inclusion criteria. The worldwide pooled prevalence of any personality disorder was 7.8% (95% CI 6.1-9.5). Rates were greater in high-income countries (9.6%, 95% CI 7.9-11.3%) compared with LMICs (4.3%, 95% CI 2.6-6.1%). In univariate meta-regressions, significant heterogeneity was partly attributable to study design (two-stage v. one-stage assessment), county income (high-income countries v. LMICs) and interview administration (clinician v. trained graduate). In multiple meta-regression analysis, study design remained a significant predictor of heterogeneity. Global rates of cluster A, B and C personality disorders were 3.8% (95% CI 3.2, 4.4%), 2.8% (1.6, 3.7%) and 5.0% (4.2, 5.9%). CONCLUSIONS: Personality disorders are prevalent globally. Nevertheless, pooled prevalence rates should be interpreted with caution due to high levels of heterogeneity. More large-scale studies with standardised methodologies are now needed to increase our understanding of population needs and regional variations.

Explaining why childhood abuse is a risk factor for poorer clinical course in bipolar disorder: a path analysis of 923 people with bipolar I disorder.

BACKGROUND: Childhood abuse is a risk factor for poorer illness course in bipolar disorder, but the reasons why are unclear. Trait-like features such as affective instability and impulsivity could be part of the explanation. We aimed to examine whether childhood abuse was associated with clinical features of bipolar disorder, and whether associations were mediated by affective instability or impulsivity. METHODS: We analysed data from 923 people with bipolar I disorder recruited by the Bipolar Disorder Research Network. Adjusted associations between childhood abuse, affective instability and impulsivity and eight clinical variables were analysed. A path analysis examined the direct and indirect links between childhood abuse and clinical features with affective instability and impulsivity as mediators. RESULTS: Affective instability significantly mediated the association between childhood abuse and earlier age of onset [effect estimate (θ)/standard error (SE): 2.49], number of depressive (θ/SE: 2.08) and manic episodes/illness year (θ/SE: 1.32), anxiety disorders (θ/SE: 1.98) and rapid cycling (θ/SE: 2.25). Impulsivity significantly mediated the association between childhood abuse and manic episodes/illness year (θ/SE: 1.79), anxiety disorders (θ/SE: 1.59), rapid cycling (θ/SE: 1.809), suicidal behaviour (θ/SE: 2.12) and substance misuse (θ/SE: 3.09). Measures of path analysis fit indicated an excellent fit to the data. CONCLUSIONS: Affective instability and impulsivity are likely part of the mechanism of why childhood abuse increases risk of poorer clinical course in bipolar disorder, with each showing some selectivity in pathways. They are potential novel targets for intervention to improve outcome in bipolar disorder.

Psychopathological outcomes of adolescent borderline personality disorder symptoms.

OBJECTIVE: Despite considerable morbidity and functional losses associated with adolescent borderline personality disorder, little is known about psychopathological outcomes. This study examined associations between adolescent borderline personality disorder symptoms and subsequent depressive, psychotic and hypomanic symptoms. METHODS: We used data from the Avon Longitudinal Study of Parents and Children. Participants were adolescents living in the community who had data for all longitudinal outcomes (N = 1758). We used logistic regression and path analysis to investigate associations between borderline personality disorder (five or more probable/definite symptoms) reported at age 11-12 years and depressive and psychotic symptoms reported at age 12 and 18, and lifetime hypomanic symptoms reported at age 22-23 years. RESULTS: Adolescent borderline personality disorder symptoms were associated with psychotic symptoms (odds ratio: 2.36, confidence interval: [1.82, 3.06]), diagnosis of depression at age 18 years (odds ratio: 1.30, confidence interval: [1.03, 1.64]) and hypomanic symptoms (odds ratio: 2.89, confidence interval: [2.40, 3.48]) at 22-23 years. Path analysis controlling for associations between all outcomes indicated that borderline personality disorder symptoms were independently associated with depressive symptoms (ß = 0.97, p < 0.001) at 12 years and hypomanic (ß = 0.58, p < 0.01) symptoms at 22-23 years. Borderline personality disorder symptoms were also associated with psychotic symptoms at age 12 years (ß = 0.58, p < 0.01), which were linked (ß = 0.34, p < 0.01) to psychotic symptoms at age 18 years. CONCLUSION: Adolescents with borderline personality disorder symptoms are at future risk of psychotic and hypomanic symptoms, and a diagnosis of depression. Future risk is independent of associations between psychopathological outcomes, indicating that adolescent borderline personality disorder symptoms have multifinal outcomes. Increasing awareness of borderline personality disorder in early adolescence could facilitate timely secondary prevention of these symptoms subsequently, helping to prevent future psychopathology.

Clinical and cost-effectiveness of contingency management for cannabis use in early psychosis: the CIRCLE randomised clinical trial.

BACKGROUND: Cannabis is the most commonly used illicit substance amongst people with psychosis. Continued cannabis use following the onset of psychosis is associated with poorer functional and clinical outcomes. However, finding effective ways of intervening has been very challenging. We examined the clinical and cost-effectiveness of adjunctive contingency management (CM), which involves incentives for abstinence from cannabis use, in people with a recent diagnosis of psychosis. METHODS: CIRCLE was a pragmatic multi-centre randomised controlled trial. Participants were recruited via Early Intervention in Psychosis (EIP) services across the Midlands and South East of England. They had had at least one episode of clinically diagnosed psychosis (affective or non-affective); were aged 18 to 36; reported cannabis use in at least 12 out of the previous 24 weeks; and were not currently receiving treatment for cannabis misuse, or subject to a legal requirement for cannabis testing. Participants were randomised via a secure web-based service 1:1 to either an experimental arm, involving 12 weeks of CM plus a six-session psychoeducation package, or a control arm receiving the psychoeducation package only. The total potential voucher reward in the CM intervention was £240. The primary outcome was time to acute psychiatric care, operationalised as admission to an acute mental health service (including community alternatives to admission). Primary outcome data were collected from patient records at 18 months post-consent by assessors masked to allocation. The trial was registered with the ISRCTN registry, number ISRCTN33576045. RESULTS: Five hundred fifty-one participants were recruited between June 2012 and April 2016. Primary outcome data were obtained for 272 (98%) in the CM (experimental) group and 259 (95%) in the control group. There was no statistically significant difference in time to acute psychiatric care (the primary outcome) (HR 1.03, 95% CI 0.76, 1.40) between groups. By 18 months, 90 (33%) of participants in the CM group, and 85 (30%) of the control groups had been admitted at least once to an acute psychiatric service. Amongst those who had experienced an acute psychiatric admission, the median time to admission was 196 days (IQR 82, 364) in the CM group and 245 days (IQR 99, 382) in the control group. Cost-effectiveness analyses suggest that there is an 81% likelihood that the intervention was cost-effective, mainly resulting from higher mean inpatient costs for the control group compared with the CM group; however, the cost difference between groups was not statistically significant. There were 58 adverse events, 27 in the CM group and 31 in the control group. CONCLUSIONS: Overall, these results suggest that CM is not an effective intervention for improving the time to acute psychiatric admission or reducing cannabis use in psychosis, at least at the level of voucher reward offered.

Can curriculum design influence medical students' attitudes to psychiatry? A comparison of two different approaches.

Medical students with poor attitudes toward psychiatry are unlikely to choose it as a career, and current psychiatry recruitment is inadequate for future NHS needs. Amending medical school curricula has been suggested as one solution. We performed a unique naturalistic mixed-methods cross-sectional survey of two sequential cohorts in a UK medical school, before and after the restructuring of the entire MBChB curriculum. As well as increasing integration with other specialties, the emphasis placed on psychiatry increased throughout the course, but the final psychiatry block reduced from 8 to 6 weeks. Students experiencing the refreshed curriculum had better attitudes to psychiatry and psychiatric patients and were more positive about psychiatry as a career for themselves and others, compared to students on the old curriculum. This was demonstrated both quantitatively using validated rating scales (12/30 questions ATP-30 and 1/6 questions PEAK-6) and qualitatively using free-text responses. Restructuring undergraduate medical curricula to enhance integration may yield added value, including the potential to improve attitudes to specialties previously learned in silos, such as psychiatry. This may improve recruitment and the understanding of mental health for all future doctors.

Neurotrophins, cytokines, oxidative stress mediators and mood state in bipolar disorder: systematic review and meta-analyses.

BACKGROUND: A reliable biomarker signature for bipolar disorder sensitive to illness phase would be of considerable clinical benefit. Among circulating blood-derived markers there has been a significant amount of research into inflammatory markers, neurotrophins and oxidative stress markers.AimsTo synthesise and interpret existing evidence of inflammatory markers, neurotrophins and oxidative stress markers in bipolar disorder focusing on the mood phase of illness. METHOD: Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a systematic review was conducted for studies investigating peripheral biomarkers in bipolar disorder compared with healthy controls. We searched Medline, Embase, PsycINFO, SciELO and Web of Science, and separated studies by bipolar mood phase (mania, depression and euthymia). Extracted data on each biomarker in separate mood phases were synthesised using random-effects model meta-analyses. RESULTS: In total, 53 studies were included, comprising 2467 cases and 2360 controls. Fourteen biomarkers were identified from meta-analyses of three or more studies. No biomarker differentiated mood phase in bipolar disorder individually. Biomarker meta-analyses suggest a combination of high-sensitivity C-reactive protein/interleukin-6, brain derived neurotrophic factor/tumour necrosis factor (TNF)-α and soluble TNF-α receptor 1 can differentiate specific mood phase in bipolar disorder. Several other biomarkers of interest were identified. CONCLUSIONS: Combining biomarker results could differentiate individuals with bipolar disorder from healthy controls and indicate a specific mood-phase signature. Future research should seek to test these combinations of biomarkers in longitudinal studies.Declaration of interestNone.