How much change is enough? Evidence from a longitudinal study on depression in UK primary care.

BACKGROUND: The Patient Health Questionnaire (PHQ-9), the Beck Depression Inventory (BDI-II) and the Generalised Anxiety Disorder Assessment (GAD-7) are widely used in the evaluation of interventions for depression and anxiety. The smallest reduction in depressive symptoms that matter to patients is known as the Minimum Clinically Important Difference (MCID). Little empirical study of the MCID for these scales exists. METHODS: A prospective cohort of 400 patients in UK primary care were interviewed on four occasions, 2 weeks apart. At each time point, participants completed all three questionnaires and a 'global rating of change' scale (GRS). MCID estimation relied on estimated changes in symptoms according to reported improvement on the GRS scale, stratified by baseline severity on the Clinical Interview Schedule (CIS-R). RESULTS: For moderate baseline severity, those who reported improvement on the GRS had a reduction of 21% (95% confidence interval (CI) -26.7 to -14.9) on the PHQ-9; 23% (95% CI -27.8 to -18.0) on the BDI-II and 26.8% (95% CI -33.5 to -20.1) on the GAD-7. The corresponding threshold scores below which participants were more likely to report improvement were -1.7, -3.5 and -1.5 points on the PHQ-9, BDI-II and GAD-7, respectively. Patients with milder symptoms require much larger reductions as percentage of their baseline to endorse improvement. CONCLUSIONS: An MCID representing 20% reduction of scores in these scales, is a useful guide for patients with moderately severe symptoms. If treatment had the same effect on patients irrespective of baseline severity, those with low symptoms are unlikely to notice a benefit. FUNDING: Funding. National Institute for Health Research.

Precursors and correlates of transient and persistent longitudinal profiles of psychotic experiences from late childhood through early adulthood.

BACKGROUND: Psychotic experiences are reported by 5-10% of young people, although only a minority persist and develop into psychotic disorders. It is unclear what characteristics differentiate those with transient psychotic experiences from those with persistent psychotic experiences that are more likely to be of clinical relevance. AIMS: To investigate how longitudinal profiles of psychotic experiences, created from assessments at three different time points, are influenced by early life and co-occurring factors. METHOD: Using data from 8045 individuals from a birth cohort study, longitudinal profiles of psychotic experiences based on semi-structured interviews conducted at 12, 18 and 24 years were defined. Environmental, cognitive, psychopathological and genetic determinants of these profiles were investigated, along with concurrent changes in psychopathology and cognition. RESULTS: Following multiple imputations, the distribution of longitudinal profiles of psychotic experiences was none (65.7%), transient (24.1%), low-frequency persistent (8.4%) and high-frequency persistent (1.7%). Individuals with high-frequency persistent psychotic experiences were more likely to report traumatic experiences, other psychopathology, a more externalised locus of control, reduced emotional stability and conscientious personality traits in childhood, compared with those with transient psychotic experiences. These characteristics also differed between those who had any psychotic experiences and those who did not. CONCLUSIONS: These findings indicate that the same risk factors are associated with incidence as with persistence of psychotic experiences. Thus, it might be that the severity of exposure, rather than the presence of specific disease-modifying factors, is most likely to determine whether psychotic experiences are transient or persist, and potentially develop into a clinical disorder over time.

Comparison between self-administered depression questionnaires and patients' own views of changes in their mood: a prospective cohort study in primary care.

BACKGROUND: Self-administered questionnaires are widely used in primary care and other clinical settings to assess the severity of depressive symptoms and monitor treatment outcomes. Qualitative studies have found that changes in questionnaire scores might not fully capture patients' experience of changes in their mood but there are no quantitative studies of this issue. We examined the extent to which changes in scores from depression questionnaires disagreed with primary care patients' perceptions of changes in their mood and investigated factors influencing this relationship. METHODS: Prospective cohort study assessing patients on four occasions, 2 weeks apart. Patients (N = 554) were recruited from primary care surgeries in three UK sites (Bristol, Liverpool and York) and had reported depressive symptoms or low mood in the past year [68% female, mean age 48.3 (s.d. 12.6)]. Main outcome measures were changes in scores on patient health questionnaire (PHQ-9) and beck depression inventory (BDI-II) and the patients' own ratings of change. RESULTS: There was marked disagreement between clinically important changes in questionnaire scores and patient-rated change, with disagreement of 51% (95% CI 46-55%) on PHQ-9 and 55% (95% CI 51-60%) on BDI-II. Patients with more severe anxiety were less likely, and those with better mental and physical health-related quality of life were more likely, to report feeling better, having controlled for depression scores. CONCLUSIONS: Our results illustrate the limitations of self-reported depression scales to assess clinical change. Clinicians should be cautious in interpreting changes in questionnaire scores without further clinical assessment.

Family socioeconomic position in early life and onset of depressive symptoms and depression: a prospective cohort study.

PURPOSE: To investigate whether low parental socioeconomic position (SEP) at birth is associated only with early-onset depressive symptoms in offspring. METHODS: This prospective cohort study used data on 9193 individuals (4768 females, 4425 males) from the Avon Longitudinal Study of Parents and Children. Depressive symptoms during three age periods (10-12, 12-16, 16-20 years) were assessed using the Short Mood and Feelings Questionnaire, and ICD-10 depression at age 18 was assessed using the Clinical Interview Schedule-Revised. RESULTS: Low SEP was associated with increased incidence rates of depressive symptoms in all age periods, with indicators of low standard of living showing the strongest associations. For instance, incidence rate ratios for material hardship were 1.75 (95% CI [1.42-2.15]) at 10-12 years, 1.36 (1.16-1.61) at 12-16 years and 1.39 (1.21-1.59) at 16-20 years. Low SEP was also associated with increased odds of ICD-10 depression at 18 years, ranging from OR = 1.20 (95% CI [0.94-1.52]) for manual social class to 1.74 (1.35-2.24) for material hardship. CONCLUSIONS: There was no evidence that depressive symptoms can be "subtyped" by the age of onset, because the association with low SEP was evident for early- and later-onset symptoms. If socioeconomic inequalities in early life have long-term adverse impacts on mental health, policies addressing these inequalities could benefit the mental health of the population.

The longitudinal association between external locus of control, social cognition and adolescent psychopathology.

PURPOSE: To investigate the longitudinal associations between social cognitive ability an external locus of control (externality) and adolescent psychopathology. METHODS: 7058 participants from a prospective population-based cohort provided data on externality, social communication, and emotion perception between 7 and 16 years and psychotic experiences and depressive symptoms at 12 and 18 years. Bivariate probit modelling was used to investigate associations between these risk factors and psychopathological outcomes. RESULTS: Externality was associated with psychopathology at 12 (psychotic experiences OR 1.23 95% CI 1.14, 1.33; depression OR 1.12 95% CI 1.02, 1.22) and 18 years (psychotic experiences OR 1.38 95% CI 1.23, 1.55; depression OR 1.40 95% CI 1.28, 1.52). Poor social communication was associated with depression at both ages (12 years OR 1.22 95% CI 1.11, 1.34; 18 years OR 1.21 95% CI 1.10, 1.33) and marginally associated with psychotic experiences. There was marginal evidence of a larger association between externality and psychotic experiences at 12 years (p = 0.06) and between social communication and depression at 12 years (p = 0.03). CONCLUSIONS: Externality was more strongly associated with psychotic experiences. At 18 years change in externality, between 8 and 16 years were associated with a larger increase in the risk of depression. Poor social communication was more strongly associated with depression.

Simultaneous multioutcome synthesis and mapping of treatment effects to a common scale.

OBJECTIVES: A new method is presented for both synthesizing treatment effects on multiple outcomes subject to measurement error and estimating coherent mapping coefficients between all outcomes. It can be applied to sets of trials reporting different combinations of patient- or clinician-reported outcomes, including both disease-specific measures and generic health-related quality-of-life measures. It is underpinned by a structural equation model that includes measurement error and latent common treatment effect factor. Treatment effects can be expressed on any of the test instruments that have been used. METHODS: This is illustrated in a synthesis of eight placebo-controlled trials of TNF-α inhibitors in ankylosing spondylitis, each reporting treatment effects on between two and five of a total six test instruments. RESULTS: The method has advantages over other methods for synthesis of multiple outcome data, including standardization and multivariate normal synthesis. Unlike standardization, it allows synthesis of treatment effect information from test instruments sensitive to different underlying constructs. It represents a special case of previously proposed multivariate normal models for evidence synthesis, but unlike the former, it also estimates mappings. Combining synthesis and mapping as a single operation makes more efficient use of available data than do current mapping methods and generates treatment effects that are consistent with the mappings. A limitation, however, is that it can only generate mappings to and from those instruments on which some trial data exist. CONCLUSIONS: The method should be assessed in a wide range of data sets on different clinical conditions, before it can be used routinely in health technology assessment.

External validation of a prognostic model to improve prediction of psychosis: a retrospective cohort study in primary care.

BACKGROUND: Early detection could reduce the duration of untreated psychosis. GPs are a vital part of the psychosis care pathway, but find it difficult to detect the early features. An accurate risk prediction tool, P Risk, was developed to detect these. AIM: To externally validate P Risk. DESIGN AND SETTING: This retrospective cohort study used a validation dataset of 1 647 934 UK Clinical Practice Research Datalink (CPRD) primary care records linked to secondary care records. METHOD: The same predictors (age; sex; ethnicity; social deprivation; consultations for suicidal behaviour, depression/anxiety, and substance misuse; history of consultations for suicidal behaviour; smoking history; substance misuse; prescribed medications for depression/anxiety/post-traumatic stress disorder/obsessive compulsive disorder; and total number of consultations) were used as for the development of P Risk. Predictive risk, sensitivity, specificity, and likelihood ratios were calculated for various risk thresholds. Discrimination (Harrell's C-index) and calibration were calculated. Results were compared between the development (CPRD GOLD) and validation (CPRD Aurum) datasets. RESULTS: Psychosis risk increased with values of the P Risk prognostic index. Incidence was highest in younger age groups and, in the main, higher in males. Harrell's C was 0.79 (95% confidence interval = 0.78 to 0.79) in the validation dataset and 0.77 in the development dataset. A risk threshold of 1.0% gave sensitivity of 65.9% and specificity of 86.6%. CONCLUSION: Further testing is required, but P Risk has the potential to be used in primary care to detect future risk of psychosis.

Desmopressin for prevention of bleeding for thrombocytopenic, critically ill patients undergoing invasive procedures: A randomised, double-blind, placebo-controlled feasibility trial.

Thrombocytopenic patients have an increased risk of bleeding when undergoing invasive procedures. In a multicentre, phase II, blinded, randomised, controlled feasibility trial, critically ill patients with platelet count 100 × 109/L or less were randomised 1:1 to intravenous desmopressin (0.3 µg/kg) or placebo before an invasive procedure. Forty-three participants (18.8% of those eligible) were recruited, with 41 eligible for analysis. Post-procedure bleeding occurred in one of 22 (4.5%) in the placebo arm and zero of 19 in the desmopressin arm. Despite liberal inclusion criteria, there were significant feasibility challenges recruiting patients in the critical care setting prior to invasive procedures.

SIGNET: protocol for a multicentre, single-blind prospective, group sequential, randomised controlled trial to evaluate the benefits of a single dose of simvastatin given to potential organ donors declared dead by neurological criteria on outcomes in organ recipients.

INTRODUCTION: Successful organ transplantation in patients with end-stage organ failure improves long-term survival, improves quality of life and reduces costs to the NHS. Despite an increase in the number of deceased organ donors over the last decade, there remains a considerable shortfall of suitable organs available for transplantation. Over half of UK donors are certified dead by neurological criteria following brain stem compression, which leads to severe physiological stress in the donor, combined with a hyperinflammatory state. Brain stem death-related dysfunction is an important reason for poor organ function and hence utilisation. For example, more than 30% of donation after brain stem death cardiac transplant recipients need short-term mechanical cardiac support, reflecting donor heart dysfunction.A small, randomised study previously showed improved outcomes for cardiac transplant recipients if the donor was given simvastatin. SIGNET takes inspiration from that study and hypothesises a potential reduction in damage to the heart and other organs during the period after diagnosis of death and prior to organ retrieval in donors that receive simvastatin. METHODS AND ANALYSIS: SIGNET is a multicentre, single-blind, prospective, group sequential, randomised controlled trial to evaluate the benefits of a single high dose of simvastatin given to potential organ donors diagnosed dead by neurological criteria on outcomes in all organ recipients. The trial will run across a minimum of 89 UK sites with a recruitment target of 2600 donors over 4 years. ETHICS AND DISSEMINATION: SIGNET received a favourable opinion from the London, Queen Square Research Ethics Committee (Ref: 21/LO/0412) and following approval of substantial amendment 1 in January 2023, the current protocol is version 2 (7 December 2022). Substantial amendment 1 clarified consent procedures and added additional sites and prescribers. Findings from the study will be publicly available and disseminated locally and internationally through manuscript publications in peer-reviewed journals and conference presentations at national and international platforms. TRIAL REGISTRATION NUMBER: ISRCTN11440354.

Defatting of donor transplant livers during normothermic perfusion-a randomised clinical trial: study protocol for the DeFat study.

BACKGROUND: Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes. METHODS: In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months). DISCUSSION: This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. TRIAL REGISTRATION: ISRCTN ISRCTN14957538. Registered in October 2022.

Childhood trajectories of internalising and externalising problems associated with a polygenic risk score for neuroticism in a UK birth cohort study.

Background: Neuroticism represents a personality disposition towards experiencing negative emotions more frequently and intensely. Longitudinal studies suggest that neuroticism increases risk of several psychological problems. Improved understanding of how this trait manifests in early life could help inform preventative strategies in those liable to neuroticism. Methods: This study explored how a polygenic risk score for neuroticism (NEU PRS) is expressed from infancy to late childhood across various psychological outcomes using multivariable linear and ordinal regression models. In addition, we employed a three-level mixed-effect model to characterise child internalising and externalising trajectories and estimate how a child PRS associated with both their overall levels and rates of change in 5279 children aged 3-11 in the Avon Longitudinal Study of Parents and Children cohort. Results: We found evidence that the NEU PRS was associated with a more emotionally sensitive temperament in early infancy in addition to higher emotional and behavioural problems and a higher risk of meeting diagnostic criteria for a variety of clinical disorders, particularly anxiety disorders, in childhood. The NEU PRS was associated with overall levels of internalising and externalising trajectories, with a larger magnitude of association on the internalising trajectory. The PRS was also associated with slower rates of reduction of internalising problems across childhood. Conclusions: Our findings using a large, well-characterised birth cohort study suggest that phenotypic manifestations of a PRS for adult neuroticism can be detected as early as in infancy and that this PRS associates with several mental health problems and differences in emotional trajectories across childhood.

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

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

Effective dose 50 method as the minimal clinically important difference: Evidence from depression trials.

OBJECTIVE: Previous research on the minimal clinically important difference (MCID) for depression and anxiety is based on population averages. The present study aimed to identify the MCID across the spectrum of baseline severity. STUDY DESIGN AND SETTINGS: The present analysis used secondary data from 2 randomized controlled trials for depression (n = 1,122) to calibrate the Global Rating of Change with the PHQ-9 and GAD-7. The MCID was defined as a change in scores corresponding to a 50% probability of patients "feeling better", given their baseline severity, referred to as Effective Dose 50 (ED50). RESULTS: MCID estimates depended on baseline severity and ranged from no change for very mild up to 14 points (52%) on the PHQ-9 and up to 10 points (48%) on the GAD-7 for very high severity. The average MCID estimates were 3.7 points (23%) and 3.3 (28%) for the PHQ-9 and GAD-7 respectively. CONCLUSION: The ED50 method generates MCID estimates across the spectrum of baseline severity, offering greater precision but at the cost of greater complexity relative to population average estimates. This has important implications for evaluations of treatments and clinical practice where users can use these results to tailor the MCID to specific populations according to baseline severities.

A Population-Based Cohort Study Examining the Incidence and Impact of Psychotic Experiences From Childhood to Adulthood, and Prediction of Psychotic Disorder.

OBJECTIVE: The authors investigated the incidence, course, and outcome of psychotic experiences from childhood through early adulthood in the general population and examined prediction of psychotic disorder. METHODS: This was a population-based cohort study using the semistructured Psychosis-Like Symptoms Interview at ages 12, 18, and 24 (N=7,900 with any data). Incidence rates were estimated using flexible parametric modeling, and positive predictive values (PPVs), sensitivity, specificity, and area under the curve were estimated for prediction. RESULTS: The incidence rate of psychotic experiences increased between ages 13 and 24, peaking during late adolescence. Of 3,866 participants interviewed at age 24, 313 (8.1%, 95% CI=7.2, 9.0) had a definite psychotic experience since age 12. A total of 109 individuals (2.8%) met criteria for a psychotic disorder up to age 24, of whom 70% had sought professional help. Prediction of current psychotic disorder at age 24 (N=47, 1.2%), by both self-report and interviewer-rated measures of psychotic experiences at age 18 (PPVs, 2.9% and 10.0%, respectively), was improved by incorporating information on frequency and distress (PPVs, 13.3% and 20.0%, respectively), although sensitivities were low. The PPV of an at-risk mental state at age 18 predicting incident disorder at ages 18-24 was 21.1% (95% CI=6.1, 45.6) (sensitivity, 14.3%, 95% CI=4.0, 32.7). CONCLUSIONS: The study results show a peak in incidence of psychotic experiences during late adolescence as well as an unmet need for care in young people with psychotic disorders. Because of the low sensitivity, targeting individuals in non-help-seeking samples based only on more severe symptom cutoff thresholds will likely have little impact on population levels of first-episode psychosis.

Correction: Sera selected from national STI surveillance system shows Chlamydia trachomatis PgP3 antibody correlates with time since infection and number of previous infections.

[This corrects the article DOI: 10.1371/journal.pone.0208652.].

The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial.

BACKGROUND: Depression is usually managed in primary care, but most antidepressant trials are of patients from secondary care mental health services, with eligibility criteria based on diagnosis and severity of depressive symptoms. Antidepressants are now used in a much wider group of people than in previous regulatory trials. We investigated the clinical effectiveness of sertraline in patients in primary care with depressive symptoms ranging from mild to severe and tested the role of severity and duration in treatment response. METHODS: The PANDA study was a pragmatic, multicentre, double-blind, placebo-controlled randomised trial of patients from 179 primary care surgeries in four UK cities (Bristol, Liverpool, London, and York). We included patients aged 18 to 74 years who had depressive symptoms of any severity or duration in the past 2 years, where there was clinical uncertainty about the benefit of an antidepressant. This strategy was designed to improve the generalisability of our sample to current use of antidepressants within primary care. Patients were randomly assigned (1:1) with a remote computer-generated code to sertraline or placebo, and were stratified by severity, duration, and site with random block length. Patients received one capsule (sertraline 50 mg or placebo orally) daily for one week then two capsules daily for up to 11 weeks, consistent with evidence on optimal dosages for efficacy and acceptability. The primary outcome was depressive symptoms 6 weeks after randomisation, measured by Patient Health Questionnaire, 9-item version (PHQ-9) scores. Secondary outcomes at 2, 6 and 12 weeks were depressive symptoms and remission (PHQ-9 and Beck Depression Inventory-II), generalised anxiety symptoms (Generalised Anxiety Disorder Assessment 7-item version), mental and physical health-related quality of life (12-item Short-Form Health Survey), and self-reported improvement. All analyses compared groups as randomised (intention-to-treat). The study is registered with EudraCT, 2013-003440-22 (protocol number 13/0413; version 6.1) and ISRCTN, ISRCTN84544741, and is closed to new participants. FINDINGS: Between Jan 1, 2015, and Aug 31, 2017, we recruited and randomly assigned 655 patients-326 (50%) to sertraline and 329 (50%) to placebo. Two patients in the sertraline group did not complete a substantial proportion of the baseline assessment and were excluded, leaving 653 patients in total. Due to attrition, primary outcome analyses were of 550 patients (266 in the sertraline group and 284 in the placebo group; 85% follow-up that did not differ by treatment allocation). We found no evidence that sertraline led to a clinically meaningful reduction in depressive symptoms at 6 weeks. The mean 6-week PHQ-9 score was 7·98 (SD 5·63) in the sertraline group and 8·76 (5·86) in the placebo group (adjusted proportional difference 0·95, 95% CI 0·85-1·07; p=0·41). However, for secondary outcomes, we found evidence that sertraline led to reduced anxiety symptoms, better mental (but not physical) health-related quality of life, and self-reported improvements in mental health. We observed weak evidence that depressive symptoms were reduced by sertraline at 12 weeks. We recorded seven adverse events-four for sertraline and three for placebo, and adverse events did not differ by treatment allocation. Three adverse events were classified as serious-two in the sertraline group and one in the placebo group. One serious adverse event in the sertraline group was classified as possibly related to study medication. INTERPRETATION: Sertraline is unlikely to reduce depressive symptoms within 6 weeks in primary care but we observed improvements in anxiety, quality of life, and self-rated mental health, which are likely to be clinically important. Our findings support the prescription of SSRI antidepressants in a wider group of participants than previously thought, including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or generalised anxiety disorder. FUNDING: National Institute for Health Research.

Application of causal inference methods in the analyses of randomised controlled trials: a systematic review.

BACKGROUND: Applications of causal inference methods to randomised controlled trial (RCT) data have usually focused on adjusting for compliance with the randomised intervention rather than on using RCT data to address other, non-randomised questions. In this paper we review use of causal inference methods to assess the impact of aspects of patient management other than the randomised intervention in RCTs. METHODS: We identified papers that used causal inference methodology in RCT data from Medline, Premedline, Embase, Cochrane Library, and Web of Science from 1986 to September 2014, using a forward citation search of five seminal papers, and a keyword search. We did not include studies where inverse probability weighting was used solely to balance baseline characteristics, adjust for loss to follow-up or adjust for non-compliance to randomised treatment. Studies where the exposure could not be assigned were also excluded. RESULTS: There were 25 papers identified. Nearly half the papers (11/25) estimated the causal effect of concomitant medication on outcome. The remainder were concerned with post-randomisation treatment regimens (sequential treatments, n =5 ), effects of treatment timing (n = 2) and treatment dosing or duration (n = 7). Examples were found in cardiovascular disease (n = 5), HIV (n = 7), cancer (n = 6), mental health (n = 4), paediatrics (n = 2) and transfusion medicine (n = 1). The most common method implemented was a marginal structural model with inverse probability of treatment weighting. CONCLUSIONS: Examples of studies which exploit RCT data to address non-randomised questions using causal inference methodology remain relatively limited, despite the growth in methodological development and increasing utilisation in observational studies. Further efforts may be needed to promote use of causal methods to address additional clinical questions within RCTs to maximise their value.

Sera selected from national STI surveillance system shows Chlamydia trachomatis PgP3 antibody correlates with time since infection and number of previous infections.

BACKGROUND: Seroprevalence surveys of Chlamydia trachomatis (CT) antibodies are promising for estimating age-specific CT cumulative incidence, however accurate estimates require improved understanding of antibody response to CT infection. METHODS: We used GUMCAD, England's national sexually transmitted infection (STI) surveillance system, to select sera taken from female STI clinic attendees on the day of or after a chlamydia diagnosis. Serum specimens were collected from laboratories and tested anonymously on an indirect and a double-antigen ELISA, both of which are based on the CT-specific Pgp3 antigen. We used cross-sectional and longitudinal descriptive analyses to explore the relationship between seropositivity and a) cumulative number of chlamydia diagnoses and b) time since most recent chlamydia diagnosis. RESULTS: 919 samples were obtained from visits when chlamydia was diagnosed and 812 during subsequent follow-up visits. Pgp3 seropositivity using the indirect ELISA increased from 57.1% (95% confidence interval: 53.2-60.7) on the day of a first-recorded chlamydia diagnosis to 89.6% (95%CI: 79.3-95.0) on the day of a third or higher documented diagnosis. With the double-antigen ELISA, the increase was from 61.1% (95%CI: 53.2-60.7) to 97.0% (95%CI: 88.5-99.3). Seropositivity decreased with time since CT diagnosis on only the indirect assay, to 49.3% (95%CI: 40.9-57.7) two or more years after a first diagnosis and 51.9% (95%CI: 33.2-70.0) after a repeat diagnosis. CONCLUSION: Seropositivity increased with cumulative number of infections, and decreased over time after diagnosis on the indirect ELISA, but not on the double-antigen ELISA. This is the first study to demonstrate the combined impact of number of chlamydia diagnoses, time since diagnosis, and specific ELISA on Pgp3 seropositivity. Our findings are being used to inform models estimating age-specific chlamydia incidence over time using serial population-representative serum sample collections, to enable accurate public health monitoring of chlamydia.

A randomised controlled trial assessing the severity and duration of depressive symptoms associated with a clinically significant response to sertraline versus placebo, in people presenting to primary care with depression (PANDA trial): study protocol for a randomised controlled trial.

BACKGROUND: Depressive symptoms are usually managed within primary care and antidepressant medication constitutes the first-line treatment. It remains unclear at present which people are more likely to benefit from antidepressant medication. This paper describes the protocol for a randomised controlled trial (PANDA) to investigate the severity and duration of depressive symptoms that are associated with a clinically significant response to sertraline compared to placebo, in people presenting to primary care with depression. METHODS/DESIGN: PANDA is a randomised, double blind, placebo controlled trial in which participants are individually randomised to sertraline or placebo. Eligible participants are those who are between the ages of 18 to 74; have presented to primary care with depression or low mood during the past 2 years; have not received antidepressant or anti-anxiety medication in the 8 weeks prior to enrolment in the trial and there is clinical equipoise about the benefits of selective serotonin reuptake inhibitor (SSRI) medication. Participants who consent to participate in the trial are randomised to receive either sertraline or matching placebo, starting at 50 mg daily for 1 week, increasing to 100 mg daily for up to 11 weeks (with the option of increasing to 150 mg if required). Participants, general practitioners (GPs) and the research team will be blind to treatment allocation. The primary outcome will be depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9) at 6 weeks post randomisation, measured as a continuous outcome. Secondary outcomes include depressive symptoms measured with the PHQ-9 at 2 and 12 weeks as a continuous outcome and at 2, 6 and 12 weeks as a binary outcome; follow-up scores on depressive symptoms measured with the Beck Depression Inventory-II, anxiety symptoms measured by the Generalized Anxiety Disorder-7 and quality of life measured with the Euroqol-5D-5L and Short Form-12; emotional processing task scores measured at baseline, 2 and 6 weeks; and costs associated with healthcare use, time off work and personal costs. DISCUSSION: The PANDA trial uses a simple self-administered measure to establish the severity and duration of depressive symptoms associated with a clinically significant response to sertraline. The evidence from the trial will inform primary care prescribing practice by identifying which patients are more likely to benefit from antidepressants. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN84544741 . Registered on 20 March 2014. EudraCT Number: 2013-003440-22; Protocol Number: 13/0413 (version 6.1).

The relative responsiveness of test instruments can be estimated using a meta-analytic approach: an illustration with treatments for depression.

OBJECTIVES: We present a meta-analytic method that combines information on treatment effects from different instruments from a network of randomized trials to estimate instrument relative responsiveness. STUDY DESIGN AND SETTING: Five depression-test instruments [Beck Depression Inventory (BDI I/II), Patient Health Questionnaire (PHQ9), Hamilton Rating for Depression 17 and 24 items, Montgomery-Asberg Depression Rating] and three generic quality of life measures [EuroQoL (EQ-5D), SF36 mental component summary (SF36 MCS), and physical component summary (SF36 PCS)] were compared. Randomized trials of treatments for depression reporting outcomes on any two or more of these instruments were identified. Information on the within-trial ratios of standardized treatment effects was pooled across the studies to estimate relative responsiveness. RESULTS: The between-instrument ratios of standardized treatment effects vary across trials, with a coefficient of variation of 13% (95% credible interval: 6%, 25%). There were important differences between the depression measures, with PHQ9 being the most responsive instrument and BDI the least. Responsiveness of the EQ-5D and SF36 PCS was poor. SF36 MCS performed similarly to depression instruments. CONCLUSION: Information on relative responsiveness of several test instruments can be pooled across networks of trials reporting at least two outcomes, allowing comparison and ranking of test instruments that may never have been compared directly.