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Background: Although suicide bereavement is associated with suicide and self-harm, evidence regarding mechanisms is lacking. We investigated whether depression and substance use (alcohol and/or other drugs) explain the association between partner suicide bereavement and suicide., Methods: Linkage of nationwide, longitudinal data from Denmark for the period 1980-2016 facilitated a comparison of 22 668 individuals exposed to bereavement by a partner's suicide with 913 402 individuals bereaved by a partner's death due to other causes. Using causal mediation models, we estimated the degree to which depression and substance use (considered separately) mediated the association between suicide bereavement and suicide., Results: Suicide-bereaved partners were found to have a higher risk of suicide (HR adj = 1.59, 95% CI 1.36-1.86) and of depression (OR adj 1.16, 95% CI 1.09-1.25) when compared to other-bereaved partners, but a lower risk of substance use (OR adj 0.83; 95% CI 0.78-0.88). An increased risk of suicide was found among any bereaved individuals with a depression diagnosis recorded post-bereavement (OR adj 3.92, 95% CI 3.55-4.34). Mediation analysis revealed that depression mediated 2% (1.68%; 95% CI 0.23%-3.14%; p = 0.024) of the association between suicide bereavement and suicide in partners when using bereaved controls., Conclusions: Depression is a partial mediator of the association between suicide bereavement and suicide. Efforts to prevent and optimize the treatment of depression in suicide-bereaved people could reduce their suicide risk. Our findings might be conservative because we did not include cases of depression diagnosed in primary care. Further work is needed to understand this and other mediators.

Background: This study aims to understand the mechanisms contributing to the elevated risk of depression among sexual minority older adults compared to heterosexuals. Specifically, the role of loneliness as a potential mediator is investigated to inform targeted interventions for preventing depression in sexual minority populations., Methods: Data from the English Longitudinal Study of Ageing, focusing on adults aged over 50, were analysed. Sexual orientation (sexual minority or heterosexual) and loneliness scores (UCLA scale) were assessed at wave six (2010-2011), while depressive symptoms (CESD) were assessed at wave seven (2013-14). Linear regression models and mediation analyses, using g-computation formula and adjusted for confounders, were conducted., Results: The sample included 6794 participants, with 478 (7.0 %) identifying as sexual minorities. After adjustments, sexual minorities scored higher on depressive symptoms at wave seven (mean difference): 0.23, 95 % CI 0.07 to 0.39) and loneliness at wave six (MD: 0.27, 95 % CI 0.08 to 0.46). Loneliness was positively associated with depressive symptoms (coefficient: 0.27, 95 % CI 0.26 to 0.29). In mediation analyses, loneliness explained 15 % of the association between sexual orientation and subsequent depressive symptoms., Limitations: The dataset used sexual behaviour rather than desire and identity, potentially skewing representation of sexual minorities. Additionally, transgender older adults were not included due to limited gender diversity reported within the ELSA dataset., Conclusions: Loneliness appears to be a significant modifiable mechanism contributing to the heightened risk of depressive symptoms in sexual minority older adults compared with their heterosexual counterparts., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Students define academic competence across two axes: developing skills and understanding (mastery) versus comparisons with peers (performance), and achieving goals (approach) versus avoiding failure (avoidance). We aimed to examine the longitudinal association between achievement goals and adolescent depressive symptoms., Methods: We analysed data from the Kindergarten (recruited at age 4-5 years; born between March, 1999, and February, 2000; recruited from March, 2004 to November, 2004) and Baby (recruited at age 0-1 years; born between March, 2003, and February, 2004; recruited from March, 2004 to January, 2005) cohorts of the Longitudinal Study of Australian Children. Participants were identified through the Medicare enrolment database and sampled using a randomised selection stratified by postcode to represent the Australian population. Achievement goals were measured at age 12-13 years with the Achievement Goal Questionnaire (ranges from 1 to 7 on each of the four subscales), and depressive symptoms with the Short Mood and Feelings Questionnaire (score ranges from 0 to 26, with higher scores indicating more severe symptoms) at ages 14-15 years (both cohorts) and 16-17 years (Kindergarten cohort only). Analyses were linear multilevel and traditional regressions, with confounder adjustment, for participants with available data on the exposures, confounders, and outcome., Findings: We included 3200 participants (1585 female and 1615 male) from the Kindergarten cohort and 2671 participants (1310 female and 1361 male) from the Baby cohort. A 1-point increase in mastery-approach goals was associated with decreased depressive symptom severity score (Kindergarten, -0·33 [95% CI -0·52 to -0·15]; Baby, -0·29 [-0·54 to -0·03]), while a 1-point increase in mastery-avoidance goals was associated with increased depressive symptom severity score (Kindergarten, 0·35 [95% CI 0·21 to 0·48]; Baby, 0·44 [0·25 to 0·64]). A 1-point increase in performance-avoidance goals was associated with increased depressive symptom severity score in the Kindergarten cohort but not the Baby cohort (Kindergarten, 0·26 [95% CI 0·11 to 0·41]; Baby, -0·04 [-0·27 to 0·19]). We found little evidence of an association between depressive symptom severity and performance-approach goals., Interpretation: Depressive symptoms in adolescents were associated with their achievement goals, which could be targetable risk factors for future trials to investigate whether school-based interventions that aim to enhance factors consistent with mastery goals (ie, learning skills and understanding the subject, rather than assessing competence in comparison to peers) could prevent depression in adolescents., Funding: Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society., Competing Interests: Declaration of interests GlL is chair of an NIHR-funded trial steering committee and has received funding for travel and accommodation to attend the European College of Neuropsychopharmacology Congress 2023. KL is a participant on the Murdoch Children's Research Institute Data Governance Instruments working group and declares no other competing interests. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Antidepressants are a first-line treatment for depression, yet many patients do not respond. There is a need to understand which patients have greater treatment response but there is little research on patient characteristics that moderate the effectiveness of antidepressants. This study examined potential moderators of response to antidepressant treatment., Methods: The PANDA trial investigated the clinical effectiveness of sertraline (n = 326) compared with placebo (n = 329) in primary care patients with depressive symptoms. We investigated 11 potential moderators of treatment effect (age, employment, suicidal ideation, marital status, financial difficulty, education, social support, family history of depression, life events, health and past antidepressant use). Using multiple linear regression, we investigated the appropriate interaction term for each of these potential moderators with treatment as allocated., Results: Family history of depression was the only variable with weak evidence of effect modification (p-value for interaction = 0.048), such that those with no family history of depression may have greater benefit from antidepressant treatment. We found no evidence of effect modification (p-value for interactions≥0.29) by any of the other ten variables., Conclusion: Evidence for treatment moderators was extremely limited, supporting an approach of continuing discuss antidepressant treatment with all patients presenting with moderate to severe depressive symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Archer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: This paper investigates whether age of onset of depression, duration of the last episode, number of episodes, and residual symptoms of depression and anxiety are associated with depression relapse in primary care patients who have been on long-term maintenance antidepressant treatment and no longer meet ICD10 criteria for depression., Methods: An observational cohort using data from ANTLER ( N = 478), a double-blind placebo-controlled trial. The primary outcome was time to relapse using the retrospective CIS-R. Participants were followed for 12 months., Results: Primary outcome was available for 468 participants. Time to relapse in those with more than five previous episodes of depression was shorter, hazard ratio (HR) 1.84 (95% confidence interval [CI] 1.23-2.75) compared to people with two episodes; HR 1.57 (95% CI 1.01-2.43) after adjustment. The residual symptoms of depression at baseline were also associated with increased relapse: HR 1.05 (95% CI 1.01-1.09) and HR 1.06 (95% CI 1.01-1.12) in the adjusted model. There was evidence of reduced rate of relapse in older age of onset group: HR 0.86 (95% CI 0.78-0.95); HR attenuated after adjustment HR 0.91 (95% CI 0.81-1.02). There was no evidence of an association between duration of the current episode and residual anxiety symptoms with relapse., Conclusions: The number of previous episodes and residual symptoms of depression were associated with increased likelihood of relapse. These factors could inform joint decision making when patients are considering tapering off maintenance antidepressant treatment or considering other treatments to prevent relapse.

Background: Guidelines on the management of depression recommend that practitioners use patient-reported outcome measures for the follow-up monitoring of symptoms, but there is a lack of evidence of benefit in terms of patient outcomes., Objective: To test using the Patient Health Questionnaire-9 questionnaire as a patient-reported outcome measure for monitoring depression, training practitioners in interpreting scores and giving patients feedback., Design: Parallel-group, cluster-randomised superiority trial; 1 : 1 allocation to intervention and control., Setting: UK primary care (141 group general practices in England and Wales)., Inclusion Criteria: Patients aged ≥ 18 years with a new episode of depressive disorder or symptoms, recruited mainly through medical record searches, plus opportunistically in consultations., Exclusions: Current depression treatment, dementia, psychosis, substance misuse and risk of suicide., Intervention: Administration of the Patient Health Questionnaire-9 questionnaire with patient feedback soon after diagnosis, and at follow-up 10-35 days later, compared with usual care., Primary Outcome: Beck Depression Inventory, 2nd edition, symptom scores at 12 weeks., Secondary Outcomes: Beck Depression Inventory, 2nd edition, scores at 26 weeks; antidepressant drug treatment and mental health service contacts; social functioning (Work and Social Adjustment Scale) and quality of life (EuroQol 5-Dimension, five-level) at 12 and 26 weeks; service use over 26 weeks to calculate NHS costs; patient satisfaction at 26 weeks (Medical Informant Satisfaction Scale); and adverse events., Sample Size: The original target sample of 676 patients recruited was reduced to 554 due to finding a significant correlation between baseline and follow-up values for the primary outcome measure., Randomisation: Remote computerised randomisation with minimisation by recruiting university, small/large practice and urban/rural location., Blinding: Blinding of participants was impossible given the open cluster design, but self-report outcome measures prevented observer bias. Analysis was blind to allocation., Analysis: Linear mixed models were used, adjusted for baseline depression, baseline anxiety, sociodemographic factors, and clustering including practice as random effect. Quality of life and costs were analysed over 26 weeks., Qualitative Interviews: Practitioner and patient interviews were conducted to reflect on trial processes and use of the Patient Health Questionnaire-9 using the Normalization Process Theory framework., Results: Three hundred and two patients were recruited in intervention arm practices and 227 patients were recruited in control practices. Primary outcome data were collected for 252 (83.4%) and 195 (85.9%), respectively. No significant difference in Beck Depression Inventory, 2nd edition, score was found at 12 weeks (adjusted mean difference -0.46, 95% confidence interval -2.16 to 1.26). Nor were significant differences found in Beck Depression Inventory, 2nd Edition, score at 26 weeks, social functioning, patient satisfaction or adverse events. EuroQol-5 Dimensions, five-level version, quality-of-life scores favoured the intervention arm at 26 weeks (adjusted mean difference 0.053, 95% confidence interval 0.013 to 0.093). However, quality-adjusted life-years over 26 weeks were not significantly greater (difference 0.0013, 95% confidence interval -0.0157 to 0.0182). Costs were lower in the intervention arm but, again, not significantly (-£163, 95% confidence interval -£349 to £28). Cost-effectiveness and cost-utility analyses, therefore, suggested that the intervention was dominant over usual care, but with considerable uncertainty around the point estimates. Patients valued using the Patient Health Questionnaire-9 to compare scores at baseline and follow-up, whereas practitioner views were more mixed, with some considering it too time-consuming., Conclusions: We found no evidence of improved depression management or outcome at 12 weeks from using the Patient Health Questionnaire-9, but patients' quality of life was better at 26 weeks, perhaps because feedback of Patient Health Questionnaire-9 scores increased their awareness of improvement in their depression and reduced their anxiety. Further research in primary care should evaluate patient-reported outcome measures including anxiety symptoms, administered remotely, with algorithms delivering clear recommendations for changes in treatment., Study Registration: This study is registered as IRAS250225 and ISRCTN17299295., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/42/02) and is published in full in Health Technology Assessment ; Vol. 28, No. 17. See the NIHR Funding and Awards website for further award information.

Objective: This study aimed to investigate longitudinal associations between changes in early childhood irritability, and depressive symptoms and self-harm at 14 years., Method: We used data from 7,225 children in a UK-based general population birth cohort. Childhood irritability was measured at 3, 5, and 7 years using 4 items from 2 questionnaires (the Children's Social Behaviour Questionnaire [CSBQ] and the Strengths and Difficulties Questionnaire [SDQ]). Participants reported depressive symptoms via the short Mood and Feelings Questionnaire (sMFQ) and self-harm via a single-item question, at 14 years. We used multilevel models to calculate within-child change in irritability between 3 and 7 years and examined associations between irritability, and depressive symptoms and self-harm at 14 years using linear and logistic regression models, respectively. We adjusted for child and family sociodemographic/economic characteristics, mental health difficulties, and child cognitive development., Results: Irritability at ages 5 and 7 years was positively associated with depressive symptoms and self-harm at age 14 years. Irritability that remained high between 3 and 7 years was associated with depressive symptoms and self-harm at 14 years in unadjusted (depressive symptoms: β coefficient = 0.22, 95 % CI = 0.08-0.37, p = .003; self-harm: odds ratio = 1.09, 95 % CI = 1.01-1.16, p = .019) and adjusted models (depressive symptoms: β coefficient = 0.31, 95 % CI = 0.17-0.45, p < .001; self-harm: odds ratio = 1.12, 95 % CI = 1.0.4-1.19, p = .004). Results were similar in imputed samples., Conclusion: Children with irritability that remains high between 3 and 7 years are more likely to report higher depressive symptoms and self-harm during adolescence. These findings support early intervention for children with high irritability and universal interventions in managing irritability for parents of preschool-aged children., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The role of alcohol use in the development of depression is unclear. We aimed to investigate whether alcohol dependence, but not high frequency or quantity of consumption, during adolescence increased the risk of depression in young adulthood., Methods: In this prospective cohort study, we included adolescents who were born to women recruited to the Avon Longitudinal Study of Parents and Children in Avon, UK, with delivery dates between April 1, 1991, and Dec 31, 1992. Alcohol dependence and consumption were measured at about age 16 years, 18 years, 19 years, 21 years, and 23 years using the self-reported Alcohol Use Disorders Identification Test, and at about age 18 years, 21 years, and 23 years using items corresponding to DSM-IV symptoms. The primary outcome was depression at age 24 years, assessed using the Clinical Interview Schedule Revised. Analyses were probit regressions between growth factors for alcohol dependence and consumption and depression, before and after adjustments for confounders: sex, housing tenure, maternal education, maternal depressive symptoms, parents' alcohol use, conduct problems at age 4 years, being bullied from age 12-16 years, and frequency of smoking cigarettes or cannabis. Adolescents were included in analyses if they had data from at least one timepoint for alcohol use and confounders., Findings: We included 3902 adolescents (2264 [58·0%] female; 1638 [42·0%] male) in our analysis, and 3727 (96·7%) of 3853 participants with data on ethnicity were White. After adjustments, we found a positive association between alcohol dependence at 18 years of age (latent intercept) and depression at 24 years of age (probit coefficient 0·13 [95% CI 0·02 to 0·25]; p=0·019), but no association between rate of change (linear slope) and depression (0·10 [-0·82 to 1·01]; p=0·84). There was no evidence of an association between alcohol consumption and depression (latent intercept probit coefficient -0·01 [-0·06 to 0·03]; p=0·60; linear slope 0·01 [-0·40 to 0·42]; p=0·96) after adjustments., Interpretation: Psychosocial or behavioural interventions that reduce the risk of alcohol dependence during adolescence could contribute to preventing depression in young adulthood., Funding: UK Medical Research Council and Alcohol Research UK (grant number MR/L022206/1)., Competing Interests: Declaration of interests MH has served as Trustee of Society of Study of Addiction and Regional Editor of Addiction in the past 3 years. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: We are not aware of a simple and short structured measure that retrospectively assesses time to relapse for depression. We developed the retrospective Clinical Interview Schedule Revised (rCIS-R) to assess depression relapse in the previous 12 weeks, for use in a clinical trial of maintenance antidepressant treatment. We assessed test-retest reliability and construct validity in relation to a Global Rating Question (GRQ) about worsening mood, participants stopping their study medication and Patient Health Questionnaire (PHQ-9) scores., Methods: In our study 444 participants provided data for rCIS-R, GRQ and PHQ-9 and 396 participants completed rCIS-R on two occasions about 30 minutes apart. The reliability study was nested within a randomised controlled trial (ANTLER)., Results: We found substantial test-retest agreement for the rCIS-R definition of relapse (kappa 0.84 (95%CI 0.71 to 0.97)), for individual sections and timing of relapse (Intraclass Correlation Coefficient 0.94 (95%CI 0.92 to 0.95)). Comparison of relapse with GRQ, stopping study medication and PHQ-9 supported the construct validity of the rCIS-R., Conclusions: The rCIS-R provides a reliable way of assessing relapse of depression over the previous 12 weeks. Its brevity, self-report format, simplicity of scoring and absence of training requirement makes it attractive to use in randomised controlled trials., Competing Interests: GL received fees from fortitude Law in relation to litigation on antidepressant withdrawal symptoms. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2023 Duffy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: This study aimed to develop, validate and compare the performance of models predicting post-treatment outcomes for depressed adults based on pre-treatment data., Methods: Individual patient data from all six eligible randomised controlled trials were used to develop ( k = 3, n = 1722) and test ( k = 3, n = 918) nine models. Predictors included depressive and anxiety symptoms, social support, life events and alcohol use. Weighted sum scores were developed using coefficient weights derived from network centrality statistics (models 1-3) and factor loadings from a confirmatory factor analysis (model 4). Unweighted sum score models were tested using elastic net regularised (ENR) and ordinary least squares (OLS) regression (models 5 and 6). Individual items were then included in ENR and OLS (models 7 and 8). All models were compared to one another and to a null model (mean post-baseline Beck Depression Inventory Second Edition (BDI-II) score in the training data: model 9). Primary outcome: BDI-II scores at 3-4 months., Results: Models 1-7 all outperformed the null model and model 8. Model performance was very similar across models 1-6, meaning that differential weights applied to the baseline sum scores had little impact., Conclusions: Any of the modelling techniques (models 1-7) could be used to inform prognostic predictions for depressed adults with differences in the proportions of patients reaching remission based on the predicted severity of depressive symptoms post-treatment. However, the majority of variance in prognosis remained unexplained. It may be necessary to include a broader range of biopsychosocial variables to better adjudicate between competing models, and to derive models with greater clinical utility for treatment-seeking adults with depression.

Background: Cognitive mechanisms that characterize or precede depressive symptoms are poorly understood. We investigated cross-sectional and longitudinal associations between risk taking to obtain reward and adolescent depressive symptoms in a large prospective cohort, using the Cambridge Gambling Task (CGT). We also explored sex differences., Methods: The Millennium Cohort Study (MCS) is an ongoing UK study, following the lives of 19 000 individuals born 2000/02. The CGT was completed at ages 11 ( n = 12 355) and 14 ( n = 10 578). Our main exposure was the proportion of points gambled, when the odds of winning were above chance (risk-taking to obtain reward). Outcomes were emotional symptoms (Strengths and Difficulties Questionnaire, SDQ) at age 11 and depressive symptoms (short Mood and Feelings Questionnaire, sMFQ) at age 14. We calculated cross-sectional and longitudinal associations, using linear regressions., Results: In univariable models, there was evidence of cross-sectional associations between risk-taking and SDQ/sMFQ scores, but these associations disappeared after we adjusted for sex. Longitudinally, there was weak evidence of an association between risk-taking and depressive symptoms in females only [a 20-point increase in risk-taking at age 11 was associated with a reduction of 0.31 sMFQ points at age 14 (95% CI -0.60 to -0.02)]. At both time-points, females were less risk-taking than males., Conclusions: We found no convincing evidence of a relationship between risk-taking to obtain reward and depressive symptoms. There were large sex differences in risk-taking, but these do not appear to contribute to the female preponderance of depressive symptoms in adolescence.

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.

Importance: Socioeconomic factors are associated with the prevalence of depression, but their associations with prognosis are unknown. Understanding this association would aid in the clinical management of depression., Objective: To determine whether employment status, financial strain, housing status, and educational attainment inform prognosis for adults treated for depression in primary care, independent of treatment and after accounting for clinical prognostic factors., Data Sources: The Embase, International Pharmaceutical Abstracts, MEDLINE, PsycINFO, and Cochrane (CENTRAL) databases were searched from database inception to October 8, 2021., Study Selection: Inclusion criteria were as follows: randomized clinical trials that used the Revised Clinical Interview Schedule (CIS-R; the most common comprehensive screening and diagnostic measure of depressive and anxiety symptoms in primary care randomized clinical trials), measured socioeconomic factors at baseline, and sampled patients with unipolar depression who sought treatment for depression from general physicians/practitioners or who scored 12 or more points on the CIS-R. Exclusion criteria included patients with depression secondary to a personality or psychotic disorder or neurologic condition, studies of bipolar or psychotic depression, studies that included children or adolescents, and feasibility studies. Studies were independently assessed against inclusion and exclusion criteria by 2 reviewers., Data Extraction and Synthesis: Data were extracted and cleaned by data managers for each included study, further cleaned by multiple reviewers, and cross-checked by study chief investigators. Risk of bias and quality were assessed using the Quality in Prognosis Studies (QUIPS) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tools, respectively. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses-Individual Participant Data (PRISMA-IPD) reporting guidelines., Main Outcomes and Measures: Depressive symptoms at 3 to 4 months after baseline., Results: This systematic review and individual patient data meta-analysis identified 9 eligible studies that provided individual patient data for 4864 patients (mean [SD] age, 42.5 (14.0) years; 3279 women [67.4%]). The 2-stage random-effects meta-analysis end point depressive symptom scale scores were 28% (95% CI, 20%-36%) higher for unemployed patients than for employed patients and 18% (95% CI, 6%-30%) lower for patients who were homeowners than for patients living with family or friends, in hostels, or homeless, which were equivalent to 4.2 points (95% CI, 3.6-6.2 points) and 2.9 points (95% CI, 1.1-4.9 points) on the Beck Depression Inventory II, respectively. Financial strain and educational attainment were associated with prognosis independent of treatment, but unlike employment and housing status, there was little evidence of associations after adjusting for clinical prognostic factors., Conclusions and Relevance: Results of this systematic review and meta-analysis revealed that unemployment was associated with a poor prognosis whereas home ownership was associated with improved prognosis. These differences were clinically important and independent of the type of treatment received. Interventions that address employment or housing difficulties could improve outcomes for patients with depression.

Background: Large population-based cohort studies of neuropsychological factors that characterise or precede depressive symptoms are rare. Most studies use small case-control or cross-sectional designs, which may cause selection bias and cannot test temporality. In a large UK population-based cohort, we investigated cross-sectional and longitudinal associations between inhibitory control of positive and negative information and adolescent depressive symptoms., Methods: Cohort study of 2328 UK adolescents who completed an affective go/no-go task at age 18. Depressive symptoms were assessed with the Clinical Interview Schedule Revised (CIS-R) and short Mood and Feeling Questionnaire (sMFQ) at age 18, and with the sMFQ 1 year later (age 19). Analyses were multilevel and traditional linear regressions, before and after adjusting for confounders., Results: Cross-sectionally, we found little evidence that adolescents with more depressive symptoms made more inhibitory control errors [after adjustments, errors increased by 0.04% per 1 s.d. increase in sMFQ score (95% confidence interval 0.02-0.06)], but this association was not observed for the CIS-R. There was no evidence for an influence of valence. Longitudinally, there was no evidence that reduced inhibitory control was associated with future depressive symptoms., Conclusions: Inhibitory control of positive and negative information does not appear to be a marker of current or future depressive symptoms in adolescents and would not be a useful target in interventions to prevent adolescent depression. Our lack of convincing evidence for associations with depressive symptoms suggests that the affective go/no-go task is not a promising candidate for future neuroimaging studies of adolescent depression.

Objective: To investigate associations between major life events and prognosis independent of treatment type: (1) after adjusting for clinical prognostic factors and socio-demographics; (2) amongst patients with depressive episodes at least six-months long; and (3) patients with a first life-time depressive episode., Methods: Six RCTs of adults seeking treatment for depression in primary care met eligibility criteria, individual patient data (IPD) were collated from all six (n = 2858). Participants were randomized to any treatment and completed the same baseline assessment of life events, demographics and clinical prognostic factors. Two-stage random effects meta-analyses were conducted., Results: Reporting any major life events was associated with poorer prognosis regardless of treatment type. Controlling for baseline clinical factors, socio-demographics and social support resulted in minimal residual evidence of associations between life events and treatment prognosis. However, removing factors that might mediate the relationships between life events and outcomes reporting: arguments/disputes, problem debt, violent crime, losing one's job, and three or more life events were associated with considerably worse prognoses (percentage difference in 3-4 months depressive symptoms compared to no reported life events =30.3%(95%CI: 18.4-43.3))., Conclusions: Assessing for clinical prognostic factors, social support, and socio-demographics is likely to be more informative for prognosis than assessing self-reported recent major life events. However, clinicians might find it useful to ask about such events, and if they are still affecting the patient, consider interventions to tackle problems related to those events (e.g. employment support, mediation, or debt advice). Further investigations of the efficacy of such interventions will be important., (Copyright © 2021. Published by Elsevier B.V.)

Background: There has been a steady increase in the number of primary care patients receiving long-term maintenance antidepressant treatment, despite limited evidence of a benefit of this treatment beyond 8 months., Objective: The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial investigated the clinical effectiveness and cost-effectiveness of antidepressant medication in preventing relapse in UK primary care., Design: This was a Phase IV, double-blind, pragmatic, multisite, individually randomised parallel-group controlled trial, with follow-up at 6, 12, 26, 39 and 52 weeks. Participants were randomised using minimisation on centre, type of antidepressant and baseline depressive symptom score above or below the median using Clinical Interview Schedule - Revised (two categories). Statisticians were blind to allocation for the outcome analyses., Setting: General practices in London, Bristol, Southampton and York., Participants: Individuals aged 18-74 years who had experienced at least two episodes of depression and had been taking antidepressants for ≥ 9 months but felt well enough to consider stopping their medication. Those who met an International Statistical Classification of Diseases and Related Health Problems , Tenth Revision, diagnosis of depression or with other psychiatric conditions were excluded., Intervention: At baseline, participants were taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg. They were randomised to either remain on their current medication or discontinue medication after a tapering period., Main Outcome Measures: The primary outcome was the time, in weeks, to the beginning of the first depressive episode after randomisation. This was measured by a retrospective Clinical Interview Schedule - Revised that assessed the onset of a depressive episode in the previous 12 weeks, and was conducted at 12, 26, 39 and 52 weeks. The depression-related resource use was collected over 12 months from medical records and patient-completed questionnaires. Quality-adjusted life-years were calculated using the EuroQol-5 Dimensions, five-level version., Results: Between 9 March 2017 and 1 March 2019, we randomised 238 participants to antidepressant continuation (the maintenance group) and 240 participants to antidepressant discontinuation (the discontinuation group). The time to relapse of depression was shorter in the discontinuation group, with a hazard ratio of 2.06 (95% confidence interval 1.56 to 2.70; p  < 0.0001). By 52 weeks, relapse was experienced by 39% of those who continued antidepressants and 56% of those who discontinued antidepressants. The secondary analysis revealed that people who discontinued experienced more withdrawal symptoms than those who remained on medication, with the largest difference at 12 weeks. In the discontinuation group, 37% (95% confidence interval 28% to 45%) of participants remained on their randomised medication until the end of the trial. In total, 39% (95% confidence interval 32% to 45%) of participants in the discontinuation group returned to their original antidepressant compared with 20% (95% confidence interval 15% to 25%) of participants in maintenance group. The health economic evaluation demonstrated that participants randomised to discontinuation had worse utility scores at 3 months (-0.037, 95% confidence interval -0.059 to -0.015) and fewer quality-adjusted life-years over 12 months (-0.019, 95% confidence interval -0.035 to -0.003) than those randomised to continuation. The discontinuation pathway, besides giving worse outcomes, also cost more [extra £2.71 per patient over 12 months (95% confidence interval -£36.10 to £37.07)] than the continuation pathway, although the cost difference was not significant., Conclusions: Patients who discontinue long-term maintenance antidepressants in primary care are at increased risk of relapse and withdrawal symptoms. However, a substantial proportion of patients can discontinue antidepressants without relapse. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants and improve shared decision-making. The participants may not have been representative of all people on long-term maintenance treatment and we could study only a restricted range of antidepressants and doses. Identifying patients who will not relapse if they discontinued antidepressants would be clinically important., Trial Registration: Current Controlled Trials ISRCTN15969819 and EudraCT 2015-004210-26., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 69. See the NIHR Journals Library website for further project information.

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., (Copyright © 2021. Published by Elsevier Inc.)

Background: Differences in serotonergic neurotransmission could lead to sex differences in depressive symptoms and tolerability after treatment with selective serotonin reuptake inhibitors (SSRIs)., Aims: We investigated whether women have greater reductions in depressive symptoms than men after treatment with an SSRI (citalopram) compared with a noradrenaline reuptake inhibitor (reboxetine) control, and after antidepressant treatment irrespective of class. We also investigated tolerability and the influence of menopausal status., Methods: Secondary analyses of the GENPOD (GENetic and clinical Predictors Of treatment response in Depression) trial. Six hundred and one people with depression were recruited from UK primary care and randomized to citalopram or reboxetine. Beck Depression Inventory (BDI-II) score at 6 weeks was the primary outcome. Secondary outcomes included BDI-II score at 12 weeks, and physical symptoms and treatment discontinuation. We calculated main effects and interaction terms using linear and logistic regression models., Results: There was no evidence that women experienced greater reductions in depressive symptoms than men when treated with citalopram compared with reboxetine. We also found no evidence of sex differences at six or 12 weeks (irrespective of antidepressant class): men scored -0.31 (95% confidence interval (CI) -2.23 to 1.62) BDI-II points lower than women at six weeks and -0.44 (95% CI -2.62 to 1.74) points lower at 12 weeks. There was no evidence of sex differences in physical symptoms or treatment discontinuation and no evidence for an influence of menopausal status., Conclusion: Citalopram was not more effective in women compared with men and there was no difference in tolerability. Women and men had similar prognosis after SSRI treatment and similar prognosis regardless of antidepressant class. Findings were unaltered by menopausal status.

Aims: To determine whether age, gender and marital status are associated with prognosis for adults with depression who sought treatment in primary care., Methods: Medline, Embase, PsycINFO and Cochrane Central were searched from inception to 1st December 2020 for randomised controlled trials (RCTs) of adults seeking treatment for depression from their general practitioners, that used the Revised Clinical Interview Schedule so that there was uniformity in the measurement of clinical prognostic factors, and that reported on age, gender and marital status. Individual participant data were gathered from all nine eligible RCTs (N = 4864). Two-stage random-effects meta-analyses were conducted to ascertain the independent association between: (i) age, (ii) gender and (iii) marital status, and depressive symptoms at 3-4, 6-8, and 9-12 months post-baseline and remission at 3-4 months. Risk of bias was evaluated using QUIPS and quality was assessed using GRADE. PROSPERO registration: CRD42019129512. Pre-registered protocol https://osf.io/e5zup/., Results: There was no evidence of an association between age and prognosis before or after adjusting for depressive 'disorder characteristics' that are associated with prognosis (symptom severity, durations of depression and anxiety, comorbid panic disorderand a history of antidepressant treatment). Difference in mean depressive symptom score at 3-4 months post-baseline per-5-year increase in age = 0(95% CI: -0.02 to 0.02). There was no evidence for a difference in prognoses for men and women at 3-4 months or 9-12 months post-baseline, but men had worse prognoses at 6-8 months (percentage difference in depressive symptoms for men compared to women: 15.08% (95% CI: 4.82 to 26.35)). However, this was largely driven by a single study that contributed data at 6-8 months and not the other time points. Further, there was little evidence for an association after adjusting for depressive 'disorder characteristics' and employment status (12.23% (-1.69 to 28.12)). Participants that were either single (percentage difference in depressive symptoms for single participants: 9.25% (95% CI: 2.78 to 16.13) or no longer married (8.02% (95% CI: 1.31 to 15.18)) had worse prognoses than those that were married, even after adjusting for depressive 'disorder characteristics' and all available confounders., Conclusion: Clinicians and researchers will continue to routinely record age and gender, but despite their importance for incidence and prevalence of depression, they appear to offer little information regarding prognosis. Patients that are single or no longer married may be expected to have slightly worse prognoses than those that are married. Ensuring this is recorded routinely alongside depressive 'disorder characteristics' in clinic may be important.

Background: Depression is commonly perceived as a single underlying disease with a number of potential treatment options. However, patients with major depression differ dramatically in their symptom presentation and comorbidities, e.g. with anxiety disorders. There are also large variations in treatment outcomes and associations of some anxiety comorbidities with poorer prognoses, but limited understanding as to why, and little information to inform the clinical management of depression. There is a need to improve our understanding of depression, incorporating anxiety comorbidity, and consider the association of a wide range of symptoms with treatment outcomes., Method: Individual patient data from six RCTs of depressed patients (total n = 2858) were used to estimate the differential impact symptoms have on outcomes at three post intervention time points using individual items and sum scores. Symptom networks (graphical Gaussian model) were estimated to explore the functional relations among symptoms of depression and anxiety and compare networks for treatment remitters and those with persistent symptoms to identify potential prognostic indicators., Results: Item-level prediction performed similarly to sum scores when predicting outcomes at 3 to 4 months and 6 to 8 months, but outperformed sum scores for 9 to 12 months. Pessimism emerged as the most important predictive symptom (relative to all other symptoms), across these time points. In the network structure at study entry, symptoms clustered into physical symptoms, cognitive symptoms, and anxiety symptoms. Sadness, pessimism, and indecision acted as bridges between communities, with sadness and failure/worthlessness being the most central (i.e. interconnected) symptoms. Connectivity of networks at study entry did not differ for future remitters vs. those with persistent symptoms., Conclusion: The relative importance of specific symptoms in association with outcomes and the interactions within the network highlight the value of transdiagnostic assessment and formulation of symptoms to both treatment and prognosis. We discuss the potential for complementary statistical approaches to improve our understanding of psychopathology.

Background: This study aimed to investigate general factors associated with prognosis regardless of the type of treatment received, for adults with depression in primary care., Methods: We searched Medline, Embase, PsycINFO and Cochrane Central (inception to 12/01/2020) for RCTs that included the most commonly used comprehensive measure of depressive and anxiety disorder symptoms and diagnoses, in primary care depression RCTs (the Revised Clinical Interview Schedule: CIS-R). Two-stage random-effects meta-analyses were conducted., Results: Twelve (n = 6024) of thirteen eligible studies (n = 6175) provided individual patient data. There was a 31% (95%CI: 25 to 37) difference in depressive symptoms at 3-4 months per standard deviation increase in baseline depressive symptoms. Four additional factors: the duration of anxiety; duration of depression; comorbid panic disorder; and a history of antidepressant treatment were also independently associated with poorer prognosis. There was evidence that the difference in prognosis when these factors were combined could be of clinical importance. Adding these variables improved the amount of variance explained in 3-4 month depressive symptoms from 16% using depressive symptom severity alone to 27%. Risk of bias (assessed with QUIPS) was low in all studies and quality (assessed with GRADE) was high. Sensitivity analyses did not alter our conclusions., Conclusions: When adults seek treatment for depression clinicians should routinely assess for the duration of anxiety, duration of depression, comorbid panic disorder, and a history of antidepressant treatment alongside depressive symptom severity. This could provide clinicians and patients with useful and desired information to elucidate prognosis and aid the clinical management of depression.

Objective: Depressed patients rate social support as important for prognosis, but evidence for a prognostic effect is lacking. We aimed to test the association between social support and prognosis independent of treatment type, and the severity of depression, and other clinical features indicating a more severe illness., Methods: Individual patient data were collated from all six eligible RCTs (n = 2858) of adults seeking treatment for depression in primary care. Participants were randomized to any treatment and completed the same baseline assessment of social support and clinical severity factors. Two-stage random effects meta-analyses were conducted., Results: Social support was associated with prognosis independent of randomized treatment but effects were smaller when adjusting for depressive symptoms and durations of depression and anxiety, history of antidepressant treatment, and comorbid panic disorder: percentage decrease in depressive symptoms at 3-4 months per z-score increase in social support = -4.14(95%CI: -6.91 to -1.29). Those with a severe lack of social support had considerably worse prognoses than those with no lack of social support: increase in depressive symptoms at 3-4 months = 14.64%(4.25% to 26.06%)., Conclusions: Overall, large differences in social support pre-treatment were associated with differences in prognostic outcomes. Adding the Social Support scale to clinical assessments may be informative, but after adjusting for routinely assessed clinical prognostic factors the differences in prognosis are unlikely to be of a clinically important magnitude. Future studies might investigate more intensive treatments and more regular clinical reviews to mitigate risks of poor prognosis for those reporting a severe lack of social support., (© 2021 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

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.

Background: There is a sharp increase in depression in females in mid-adolescence, but we do not understand why. Cognitive theories suggest that people with depression have negative biases in recalling self-referential information. We tested whether recall biases were more negative in girls in early and mid-adolescence and were associated with depressive symptoms., Methods: 315 young and 263 mid-adolescents (11-12 and 13-15 years) completed a surprise test, assessing recall of social evaluation about the self (self-referential) or another person (other-referential). The short Mood and Feelings Questionnaire measured depressive symptoms. We tested the effects of condition (self-referential/other-referential), valence (positive/negative), gender, and age group on correct recall (hits) and associations with depressive symptoms., Results: There was no evidence for gender or age differences in positive or negative self-referential recall. Self-referential positive hits were negatively associated with depressive symptoms (adjusted coefficient=-0.38, 95% CI=-0.69-0.08, p=0.01). Self-referential negative hits were positively associated with depressive symptoms (adjusted coefficient=0.45, 95% CI=0.15-0.75, p=0.003), and this association was stronger in females (adjusted interaction p=0.04)., Limitations: The reliability and validity of the recall task are unknown. We cannot provide evidence of a causal effect of recall on depressive symptoms in this cross-sectional study., Conclusions: Adolescents who recalled more self-referential negative and fewer self-referential positive words had more severe depressive symptoms. Females did not demonstrate more recall biases, but the association between self-referential negative hits and depressive symptoms was stronger in females. Negative self-referential recall may be a risk factor for depressive symptoms and is a good candidate for longitudinal studies., (Copyright © 2020. Published by Elsevier B.V.)

Background: Loneliness is experienced by a third of older adults in the UK and is a modifiable potential risk factor for depressive symptoms. It is unclear how the association between loneliness and depressive symptoms persists over time, and whether it is independent of related social constructs and genetic confounders. We aimed to investigate the association between loneliness and depressive symptoms, assessed on multiple occasions during 12 years of follow-up, in a large, nationally representative cohort of adults aged 50 years and older in England., Methods: We did a longitudinal study using seven waves of data that were collected once every 2 years between 2004 and 2017, from adults aged 50 years and older in the English Longitudinal Study of Ageing (ELSA). The exposure was loneliness at baseline (wave two), measured with the short 1980 revision of the University of California, Los Angeles Loneliness Scale (R-UCLA). The primary outcome was a score indicating severity of depression measured at six subsequent timepoints (waves three to eight), using the eight-item version of the Centre for Epidemiologic Studies Depression Scale (CES-D). Analyses were linear multilevel regressions, before and after adjusting for social isolation, social support, polygenic risk scores, and other sociodemographic and health-related confounders. The secondary outcome was depression diagnosis, measured using a binary version of the CES-D., Findings: 4211 (46%) of 9171 eligible participants had complete data on exposure, outcome, and confounders, and were included in our complete case sample. After all adjustments, a 1-point increase in loneliness score was associated with a 0·16 (95% CI 0·13-0·19) increase in depressive symptom severity score (averaged across all follow-ups). We estimated a population attributable fraction for depression associated with loneliness of 18% (95% CI 12-24) at 1 year of follow-up and 11% (3-19) at the final follow-up (wave eight), suggesting that 11-18% of cases of depression could potentially be prevented if loneliness were eliminated. Associations between loneliness and depressive symptoms remained after 12 years of follow-up, although effect sizes were smaller with longer follow-up., Interpretation: Irrespective of other social experiences, higher loneliness scores at baseline were associated with higher depression symptom severity scores during 12 years of follow-up among adults aged 50 years and older. Interventions that reduce loneliness could prevent or reduce depression in older adults, which presents a growing public health problem worldwide., Funding: National Institute on Aging and a consortium of UK Government departments coordinated by the National Institute for Health Research., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: Dysfunctional reward processing is a leading candidate mechanism for the development of certain depressive symptoms, such as anhedonia. However, to our knowledge, there has not yet been a systematic assessment of whether and to what extent depression is associated with impairments on behavioral reward-processing tasks., Objective: To determine whether depression is associated with impairments in reward-processing behavior., Data Sources: The MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies that investigated reward processing using performance on behavioral tasks by individuals with depression and nondepressed control groups, published between January 1, 1946, and August 16, 2019., Study Selection: Studies that contained data regarding performance by depressed and healthy control groups on reward-processing tasks were included in the systematic review and meta-analysis., Data Extraction and Synthesis: Summary statistics comparing performance between depressed and healthy groups on reward-processing tasks were converted to standardized mean difference (SMD) scores, from which summary effect sizes for overall impairment in reward processing and 4 subcomponent categories were calculated. Study quality, heterogeneity, replicability-index, and publication bias were also assessed., Main Outcome and Measures: Performance on reward-processing tasks., Results: The final data set comprised 48 case-control studies (1387 healthy control individuals and 1767 individuals with major depressive disorder). The mean age was 37.85 years and 58% of the participants were women. These studies used tasks assessing option valuation (n = 9), reward bias (n = 6), reward response vigor (n = 12), reinforcement learning (n = 20), and grip force (n = 1). Across all tasks, depression was associated with small to medium impairments in reward-processing behavior (SMD = 0.345; 95% CI, 0.209-0.480). When examining reward-processing subcomponent categories, impairment was associated with tasks assessing option valuation (SMD = 0.309; 95% CI, 0.147-0.471), reward bias (SMD = 0.644; 95% CI, 0.270-1.017), and reinforcement learning (SMD = 0.352; 95% CI, 0.115-0.588) but not reward response vigor (SMD = 0.083; 95% CI, -0.144 to 0.309). The medication status of the major depressive disorder sample did not explain any of the variance in the overall effect size. There was significant between-study heterogeneity overall and in all subcomponent categories other than option valuation. Significant publication bias was identified overall and in the reinforcement learning category., Conclusions and Relevance: Relative to healthy control individuals, individuals with depression exhibit reward-processing impairments, particularly for tests of reward bias, option valuation, and reinforcement learning. Understanding the neural mechanisms driving these associations may assist in designing novel interventions.

Objectives: Cognitive behavioral therapy (CBT) is an effective treatment for depression. Different CBT delivery formats (face-to-face [F2F], multimedia, and hybrid) and intensities have been used to expand access to the treatment. The aim of this study is to estimate the long-term cost-effectiveness of different CBT delivery modes., Methods: A decision-analytic model was developed to evaluate the cost-effectiveness of different CBT delivery modes and variations in intensity in comparison with treatment as usual (TAU). The model covered an average treatment period of 4 months with a 5-year follow-up period. The model was populated using a systematic review of randomized controlled trials and various sources from the literature., Results: Incremental cost-effectiveness ratios of treatments compared with the next best option after excluding all the dominated and extended dominated options are: £209/quality-adjusted life year (QALY) for 6 (sessions) × 30 (minutes) F2F-CBT versus TAU; £4 453/QALY for 8 × 30 F2F versus 6 × 30 F2F; £12 216/QALY for 8 × 60 F2F versus 8 × 30 F2F; and £43 072/QALY for 16 × 60 F2F versus 8 × 60 F2F. The treatment with the highest net monetary benefit for thresholds of £20 000 to £30 000/QALY was 8 × 30 F2F-CBT. Probabilistic sensitivity analysis illustrated 6 × 30 F2F-CBT had the highest probability (32.8%) of being cost-effective at £20 000/QALY; 16 × 60 F2F-CBT had the highest probability (31.0%) at £30 000/QALY., Conclusions: All CBT delivery modes on top of TAU were found to be more cost-effective than TAU alone. Four F2F-CBT options (6 × 30, 8 × 30, 8 × 60, 16 × 60) are on the cost-effectiveness frontier. F2F-CBT with intensities of 6 × 30 and 16 × 60 had the highest probabilities of being cost-effective. The results, however, should be interpreted with caution owing to the high level of uncertainty., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Depression and harmful alcohol consumption contribute significantly to the global health burden, but in young adults, this relationship is under-researched and conflicted. The aim of this study was to determine the sex-based prevalence and the association between internalising disorders such as depression and alcohol use disorders., Method: Using the Avon Longitudinal Study of Parents and Children, we assessed the sex-specific prevalence of International Classification of Diseases,Tenth Revision diagnosed generalised anxiety disorder (GAD), depression and fear-based anxieties (FBA) at 24 years (n=3572). We examined the association between internalising disorders and alcohol consumption using the Alcohol Use Disorder Identification Test for Consumption 5+ threshold and Diagnostic and Statistical Manual on Mental Disorders defined criteria for alcohol dependence., Results: Women reported more GAD (11.6% vs 6.5%), depression (13.4% vs 6.9%) and FBA (1.3% vs 0.5%) than men (p<0.001). Harmful drinking, after adjustment for sex and socioeconomic status, was associated with a higher prevalence of depression (OR 1.8, 95% CI 1.3 to 2.4, p<0.001), anxiety (OR 1.4, 95% CI 1.0 to 2.0, p<0.001) and FBA (OR 2.4, 95% CI 1.04 to 5.56, p=0.009) compared with lower-risk drinkers. In contrast, hazardous drinking was associated with a lower prevalence of GAD (OR 0.69, 95% CI 0.54 to 0.88) and depression (OR 0.68, 95% CI 0.54 to 0.86) compared with lower-risk drinkers., Conclusions: Young adults in the UK who drink harmfully are more likely to have depression and other internalising disorders. Further research should test whether there is a J-shaped relationship between alcohol consumption and mental health in young people and whether this varies across the life course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Little is known about the burden of common mental disorders in Russia despite high levels of suicide and alcohol-related mortality. Here we investigated levels of symptoms, self-reports of ever having received a diagnosis and treatment of anxiety and depression in two Russian cities., Methods: The study population was men and women aged 35-69 years old participating in cross-sectional population-based studies in the cities of Arkhangelsk and Novosibirsk (2015-18). Participants completed an interview which included the PHQ-9 and GAD-7 scales, questions on whether participants had ever received a diagnosis of depression or anxiety, and health service use in the past year. Participants also reported current medication use and medications were coded in line with the WHO anatomical therapeutic classification (ATC). Depression was defined as PHQ-9 ≥ 10 and Anxiety as GAD-7 ≥ 10., Results: Age-standardised prevalence of PHQ-9 ≥ 10 was 10.7% in women and 5.4% in men (GAD-7 ≥ 10 6.2% in women; 3.0% in men). Among those with PHQ-9 ≥ 10 17% reported ever having been diagnosed with depression (equivalent finding for anxiety 29%). Only 1.5% of those with PHQ-9 ≥ 10 reported using anti-depressants and 0.6% of those with GAD-7 ≥ 10 reported using anxiolytics. No men with PHQ-9 ≥ 10 and/or GAD-7 ≥ 10 reported use of anti-depressants or anxiolytics. Use of health services increased with increasing severity of both depression and anxiety., Conclusion: There was a large gap between symptoms and reporting of past diagnosis and treatment of common mental disorders in two Russian cities. Interventions aimed at improving mental health literacy and reducing stigma could be of benefit in closing this substantial treatment gap.

Background: Depression and anxiety symptoms are common among university students, but many do not receive treatment. This is often because of lack of availability, reluctance to seek help, and not meeting the diagnostic criteria required to access services. Internet-based interventions, including smartphone apps, can overcome these issues. However, a large number of apps are available, each with little evidence of their effectiveness., Objective: This study aims to evaluate for the first time the effectiveness of a self-guided mobile app, Feel Stress Free, for the treatment of depression and anxiety symptoms in students., Methods: A web-based randomized controlled trial compared a cognitive behavioral therapy (CBT)-based mobile app Feel Stress Free with a wait-list control. University students self-identified as experiencing symptoms of anxiety or depression and were randomized to 6 weeks of intervention (n=84) or control (n=84), unblinded. The app is self-guided and incorporates behavioral relaxation activities, mood tracking and thought challenging, and minigames. Participants completed the Hospital Anxiety and Depression Scale online at baseline and every fortnight., Results: At week 6, the primary end point, there was evidence that the Feel Stress Free app reduced depression symptoms (mean difference -1.56; 95% CI -2.67 to -0.44; P=.006) but only very weak evidence that it reduced anxiety symptoms (mean difference -1.36; 95% CI -2.93 to 0.21; P=.09). At week 4, there was evidence to support the effectiveness of the intervention for anxiety symptoms (mean difference -1.94; 95% CI -3.11 to -0.77; P=.001) and, though weaker, depression symptoms (mean difference -1.08; 95% CI -2.12 to -0.04; P=.04). At week 6, 83% (34/41) of participants indicated that they were using the app weekly or more frequently., Conclusions: The Feel Stress Free app is a promising mobile intervention for treating symptoms of anxiety and depression in students and overcomes many of the barriers to traditional CBT. Further research is needed to establish its effectiveness at and beyond 6 weeks., Trial Registration: ClinicalTrials.gov NCT03032952; https://clinicaltrials.gov/ct2/show/NCT03032952., (©Tayla McCloud, Rebecca Jones, Gemma Lewis, Vaughan Bell, Elias Tsakanikos. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 31.07.2020.)

Background: Loneliness is common among people with mental health problems and predicts poorer recovery from depression and anxiety. Needs for support with loneliness and social relationships are often under-addressed in mental health services. The Community Navigator programme was designed to reduce loneliness for adults (aged 18 and above) with complex depression or anxiety who were using secondary mental health services. Acceptability and feasibility of the programme and a trial evaluation were tested in a feasibility randomised controlled trial with qualitative evaluation., Methods: Forty participants with depression or anxiety using secondary mental health services were recruited from mental health services in two London sites and randomised to receive: the Community Navigator programme over six months in addition to routine care (n = 30); or routine care (n = 10). Measures of loneliness, depression, other clinical and social outcomes and service use were collected at baseline and six-months follow-up. Levels of engagement in the programme and rates of trial recruitment and retention were assessed. Programme delivery was assessed through session logs completed by Community Navigators. The acceptability of the programme was explored through qualitative interviews (n = 32) with intervention group participants, their family and friends, programme providers and other involved staff., Results: Forty participants were recruited in four months from 65 eligible potential participants asked. No one withdrew from the trial. Follow-up interviews were completed with 35 participants (88%). Process records indicated the programme was delivered as intended: there was a median of seven meetings with their Community Navigator (of a maximum ten) per treatment group participant. Qualitative interviews indicated good acceptability of the programme to stakeholders, and potential utility in reducing loneliness and depression and anxiety., Conclusions: A definitive, multi-site randomised controlled trial is recommended to evaluate the effectiveness and cost-effectiveness of the Community Navigator programme for people with complex anxiety and depression in secondary mental health services., Competing Interests: The authors have declared that no competing interests exist.

Background: Around one in ten adults take antidepressants for depression in England, and their long-term use is increasing. Some need them to prevent relapse, but 30-50% could possibly stop them without relapsing and avoid adverse effects and complications of long-term use. However, stopping is not always easy due to withdrawal symptoms and a fear of relapse of depression. When general practitioners review patients on long-term antidepressants and recommend to those who are suitable to stop the medication, only 6-8% are able to stop. The Reviewing long-term antidepressant use by careful monitoring in everyday practice (REDUCE) research programme aims to identify safe and cost-effective ways of helping patients taking long-term antidepressants taper off treatment when appropriate., Methods: Design: REDUCE is a two-arm, 1:1 parallel group randomised controlled trial, with randomisation clustered by participating family practices., Setting: England and north Wales., Population: patients taking antidepressants for longer than 1 year for a first episode of depression or longer than 2 years for repeated episodes of depression who are no longer depressed and want to try to taper off their antidepressant use., Intervention: provision of 'ADvisor' internet programmes to general practitioners or nurse practitioners and to patients designed to support antidepressant withdrawal, plus three patient telephone calls from a psychological wellbeing practitioner. The control arm receives usual care. Blinding of patients, practitioners and researchers is not possible in an open pragmatic trial, but statistical and health economic data analysts will remain blind to allocation., Outcome Measures: the primary outcome is self-reported nine-item Patient Health Questionnaire at 6 months for depressive symptoms., Secondary Outcomes: depressive symptoms at other follow-up time points, anxiety, discontinuation of antidepressants, social functioning, wellbeing, enablement, quality of life, satisfaction, and use of health services for costs., Sample Size: 402 patients (201 intervention and 201 controls) from 134 general practices recruited over 15-18 months, and followed-up at 3, 6, 9 and 12 months. A qualitative process evaluation will be conducted through interviews with 15-20 patients and 15-20 practitioners in each arm to explore why the interventions were effective or not, depending on the results., Discussion: Helping patients reduce and stop antidepressants is often challenging for practitioners and time-consuming for very busy primary care practices. If REDUCE provides evidence showing that access to internet and telephone support enables more patients to stop treatment without increasing depression we will try to implement the intervention throughout the National Health Service, publishing practical guidance for professionals and advice for patients to follow, publicised through patient support groups., Trial Registration: ISRCTN:12417565. Registered on 7 October 2019.

Background: Evidence exists that maternal depression in the perinatal period has an adverse effect on a range of early childhood outcomes and increases the risk of offspring depression during adolescence. However, the association between maternal depression during the perinatal period and offspring psychotic experiences has not been investigated. We aimed to investigate whether there is an association between maternal antenatal or postnatal depression and offspring psychotic experiences at 18 years of age., Methods: This longitudinal study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort, which recruited 14 541 pregnant women with an estimated delivery date between April 1, 1991, and Dec 31, 1992. Perinatal depression was measured using the Edinburgh Postnatal Depression Scale (EPDS); offspring psychotic experiences at 18 years of age were measured using the Psychosis-Like Symptom Interview. Offspring of mothers with complete data on maternal perinatal depression measures, and complete data on outcome (psychotic experiences) and confounding variables were included in the main analysis. For the main analysis, we used logistic regression to examine the associations between maternal depression (antenatal and postnatal) and offspring psychotic experiences at the age of 18 years. We used biprobit regression to model the association between maternal antenatal depression and the two offspring outcomes (psychotic experiences and depression) at 18 years of age jointly., Findings: 3067 offspring for whom data were available on maternal perinatal depression and offspring psychotic experiences aged 18 years were included in analyses. Maternal antenatal depressive symptoms were associated with offspring psychotic experiences at 18 years of age, with an unadjusted odds ratio (OR) of 1·38 (95% CI 1·18-1·61, p=0·0001) and after adjustment for confounders, an OR of 1·26 (1·06-1·49, p=0·0074). Maternal antenatal depressive symptoms were associated with both offspring psychotic experiences at the age of 18 years (n=2830, OR for a 5-point increase in EPDS score: 1·32 [95% CI 1·16-1·51], p<0·0001) and offspring depression at 18 years (OR for a 5-point increase in EPDS score: 1·18 [1·03-1·34], p=0·016). From joint modelling, there was no evidence that the association between maternal antenatal depression and offspring psychotic experiences differed in strength compared with offspring depression (p=0·19)., Interpretation: The offspring of mothers who experience depression in the perinatal period are more likely to report psychotic experiences at 18 years of age. If the association is found to be causal, it would strengthen the case for identifying and treating maternal depression during and after pregnancy., Funding: UK Medical Research Council and the Wellcome Trust., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Identifying modifiable risk factors is essential to reduce the prevalence adolescent depression. Self-report data suggest that physical activity and sedentary behaviour might be associated with depressive symptoms in adolescents. We examined associations between depressive symptoms and objectively measured physical activity and sedentary behaviour in adolescents., Methods: From a population-based cohort of adolescents whose mothers were invited to participate in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, we included participants with at least one accelerometer recording and a Clinical Interview Schedule-Revised (CIS-R) depression score at age 17·8 years (reported as age 18 years hereafter). Amounts of time spent in sedentary behaviour and physical activity (light or moderate-to-vigorous) were measured with accelerometers at around 12 years, 14 years, and 16 years of age. Total physical activity was also recorded as count per minute (CPM), with raw accelerometer counts averaged over 60 s epochs. Associations between the physical activity and sedentary behaviour variables and depression (CIS-R) scores at age 18 years were analysed with regression and group-based trajectory modelling., Findings: 4257 adolescents from the 14 901 enrolled in the ALSPAC study had a CIS-R depression score at age 18 years. Longitudinal analyses included 2486 participants at age 12 years, 1938 at age 14 years, and 1220 at age 16 years. Total follow-up time was 6 years. Total physical activity decreased between 12 years and 16 years of age, driven by decreasing durations of light activity (mean 325·66 min/day [SD 58·09] at 12 years; 244·94 min/day [55·08] at 16 years) and increasing sedentary behaviour (430·99 min/day [65·80]; 523·02 min/day [65·25]). Higher depression scores at 18 years were associated with a 60 min/day increase in sedentary behaviour at 12 years (incidence rate ratio [IRR] 1·111 [95% CI 1·051-1·176]), 14 years (1·080 [1·012-1·152]), and 16 years of age (1·107 [1·015-1·208]). Depression scores at 18 years were lower for every additional 60 min/day of light activity at 12 years (0·904 [0·850-0·961]), 14 years (0·922 [0·857-0·992]), and 16 years of age (0·889 [0·809-0·974]). Group-based trajectory modelling across 12-16 years of age identified three latent subgroups of sedentary behaviour and activity levels. Depression scores were higher in those with persistently high (IRR 1·282 [95% CI 1·061-1·548]) and persistently average (1·249 [1·078-1·446]) sedentary behaviour compared with those with persistently low sedentary behaviour, and were lower in those with persistently high levels of light activity (0·804 [0·652-0·990]) compared with those with persistently low levels of light activity. Moderate-to-vigorous physical activity (per 15 min/day increase) at age 12 years (0·910 [0·857-0·966]) and total physical activity (per 100 CPM increase) at ages 12 years (0·941 [0·910-0·972]) and 14 years (0·965 [0·932-0·999]), were negatively associated with depressive symptoms., Interpretation: Sedentary behaviour displaces light activity throughout adolescence, and is associated with a greater risk of depressive symptoms at 18 years of age. Increasing light activity and decreasing sedentary behaviour during adolescence could be an important target for public health interventions aimed at reducing the prevalence of depression., Funding: Details of funding are provided in the Acknowledgments., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Two longitudinal studies have shown that depressive symptoms in women with eating disorders might improve in the antenatal and early postnatal periods. No study has followed up women beyond 8 months postnatal., Aims: To investigate long-term trajectories of depressive symptoms in mothers with lifetime self-reported eating disorders., Method: Using data from the Avon Longitudinal Study of Parents and Children and multilevel growth curves we modelled trajectories of depressive symptoms from the 18th week of pregnancy to 18 years postnatal in women with lifetime self-reported anorexia nervosa, bulimia nervosa or both anorexia and bulimia nervosa. As sensitivity analyses we also investigated these trajectories using quintiles of a continuous measure of body image in pregnancy., Results: Of the 9276 women in our main sample, 126 (1.4%) reported a lifetime diagnosis of anorexia nervosa, 153 (1.6%) of bulimia nervosa and 60 (0.6%) of both anorexia and bulimia nervosa. Women with lifetime eating disorders had greater depressive symptoms scores than women with no eating disorders, before and after adjustment for confounders (anorexia nervosa: 2.10, 95% CI 1.36-2.83; bulimia nervosa: 2.28, 95% CI: 1.61-2.94, both anorexia and bulimia nervosa: 2.86, 95% CI 1.81-3.90). We also observed a dose-response association between greater body image and eating concerns in pregnancy and more severe trajectories of depressive symptoms, even after adjusting for lifetime eating disorders which also remained independently associated with greater depressive symptoms., Conclusions: Women with eating disorders experience persistently greater depressive symptoms across the life-course. More training for practitioners and midwives on how to recognise eating disorders in pregnancy could help to identify depressive symptoms and reduce the long-term burden of disease resulting from this comorbidity.

Background: Meta-analyses confirm increased circulating C-reactive protein (CRP) levels in depression. Longitudinal studies have linked one-off measurements of CRP at baseline with increased risk of developing depressive symptoms subsequently at follow-up, but studies with repeat CRP measures from the same individuals are scarce., Methods: We have examined whether longitudinal patterns of inflammation, based on three CRP measurements from childhood to early-adulthood, are associated with the risk of depression in early-adulthood in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort., Results: Using Gaussian mixture modelling of available CRP data from age 9, 15 and 18 years, we identified four population clusters/sub-groups reflecting different longitudinal patterns of CRP: persistently low (N=463, 29.5%); persistently high (N=371, 24%); decreasing (N=360, 23%); increasing (N=367, 23.5%). The increasing group showed a steep increase in CRP levels between adolescence and early-adulthood. Participants in this group had a higher risk of moderate/severe depression at age 18 years, compared with those with persistently low CRP; adjusted odds ratio (OR)=3.78 (95% Confidence Interval (CI), 1.46-9.81; p=0.006). The odds of moderate/severe depression were also increased for the persistently high CRP group, but this was not statistically significant; OR=2.54 (95% CI, 0.90-7.16)., Limitations: Repeat CRP measures were available for a subset, who may not be representative of all cohort participants., Conclusions: The results suggest that an increasing pattern of inflammation from adolescence to early-adulthood is associated with risk of depression in early-adulthood., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although antidepressants are often a first-line treatment for adults with moderate to severe depression, many people do not respond adequately to medication, and are said to have treatment-resistant depression (TRD). Little evidence exists to inform the most appropriate 'next step' treatment for these people., Objectives: To assess the effectiveness of standard pharmacological treatments for adults with TRD., Search Methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (March 2016), CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science (31 December 2018), the World Health Organization trials portal and ClinicalTrials.gov for unpublished and ongoing studies, and screened bibliographies of included studies and relevant systematic reviews without date or language restrictions., Selection Criteria: Randomised controlled trials (RCTs) with participants aged 18 to 74 years with unipolar depression (based on criteria from DSM-IV-TR or earlier versions, International Classification of Diseases (ICD)-10, Feighner criteria or Research Diagnostic Criteria) who had not responded to a minimum of four weeks of antidepressant treatment at a recommended dose. Interventions were: (1) increasing the dose of antidepressant monotherapy; (2) switching to a different antidepressant monotherapy; (3) augmenting treatment with another antidepressant; (4) augmenting treatment with a non-antidepressant. All were compared with continuing antidepressant monotherapy. We excluded studies of non-standard pharmacological treatments (e.g. sex hormones, vitamins, herbal medicines and food supplements)., Data Collection and Analysis: Two reviewers used standard Cochrane methods to extract data, assess risk of bias, and resolve disagreements. We analysed continuous outcomes with mean difference (MD) or standardised mean difference (SMD) and 95% confidence interval (CI). For dichotomous outcomes, we calculated a relative risk (RR) and 95% CI. Where sufficient data existed, we conducted meta-analyses using random-effects models., Main Results: We included 10 RCTs (2731 participants). Nine were conducted in outpatient settings and one in both in- and outpatients. Mean age of participants ranged from 42 - 50.2 years, and most were female. One study investigated switching to, or augmenting current antidepressant treatment with, another antidepressant (mianserin). Another augmented current antidepressant treatment with the antidepressant mirtazapine. Eight studies augmented current antidepressant treatment with a non-antidepressant (either an anxiolytic (buspirone) or an antipsychotic (cariprazine; olanzapine; quetiapine (3 studies); or ziprasidone (2 studies)). We judged most studies to be at a low or unclear risk of bias. Only one of the included studies was not industry-sponsored. There was no evidence of a difference in depression severity when current treatment was switched to mianserin (MD on Hamilton Rating Scale for Depression (HAM-D) = -1.8, 95% CI -5.22 to 1.62, low-quality evidence)) compared with continuing on antidepressant monotherapy. Nor was there evidence of a difference in numbers dropping out of treatment (RR 2.08, 95% CI 0.94 to 4.59, low-quality evidence; dropouts 38% in the mianserin switch group; 18% in the control). Augmenting current antidepressant treatment with mianserin was associated with an improvement in depression symptoms severity scores from baseline (MD on HAM-D -4.8, 95% CI -8.18 to -1.42; moderate-quality evidence). There was no evidence of a difference in numbers dropping out (RR 1.02, 95% CI 0.38 to 2.72; low-quality evidence; 19% dropouts in the mianserin-augmented group; 38% in the control). When current antidepressant treatment was augmented with mirtazapine, there was little difference in depressive symptoms (MD on Beck Depression Inventory (BDI-II) -1.7, 95% CI -4.03 to 0.63; high-quality evidence) and no evidence of a difference in dropout numbers (RR 0.50, 95% CI 0.15 to 1.62; dropouts 2% in mirtazapine-augmented group; 3% in the control). Augmentation with buspirone provided no evidence of a benefit in terms of a reduction in depressive symptoms (MD on Montgomery and Asberg Depression Rating Scale (MADRS) -0.30, 95% CI -9.48 to 8.88; low-quality evidence) or numbers of drop-outs (RR 0.60, 95% CI 0.23 to 1.53; low-quality evidence; dropouts 11% in buspirone-augmented group; 19% in the control). Severity of depressive symptoms reduced when current treatment was augmented with cariprazine (MD on MADRS -1.50, 95% CI -2.74 to -0.25; high-quality evidence), olanzapine (MD on HAM-D -7.9, 95% CI -16.76 to 0.96; low-quality evidence; MD on MADRS -12.4, 95% CI -22.44 to -2.36; low-quality evidence), quetiapine (SMD -0.32, 95% CI -0.46 to -0.18; I2 = 6%, high-quality evidence), or ziprasidone (MD on HAM-D -2.73, 95% CI -4.53 to -0.93; I2 = 0, moderate-quality evidence) compared with continuing on antidepressant monotherapy. However, a greater number of participants dropped out when antidepressant monotherapy was augmented with an antipsychotic (cariprazine RR 1.68, 95% CI 1.16 to 2.41; quetiapine RR 1.57, 95% CI: 1.14 to 2.17; ziprasidone RR 1.60, 95% CI 1.01 to 2.55) compared with antidepressant monotherapy, although estimates for olanzapine augmentation were imprecise (RR 0.33, 95% CI 0.04 to 2.69). Dropout rates ranged from 10% to 39% in the groups augmented with an antipsychotic, and from 12% to 23% in the comparison groups. The most common reasons for dropping out were side effects or adverse events. We also summarised data about response and remission rates (based on changes in depressive symptoms) for included studies, along with data on social adjustment and social functioning, quality of life, economic outcomes and adverse events., Authors' Conclusions: A small body of evidence shows that augmenting current antidepressant therapy with mianserin or with an antipsychotic (cariprazine, olanzapine, quetiapine or ziprasidone) improves depressive symptoms over the short-term (8 to 12 weeks). However, this evidence is mostly of low or moderate quality due to imprecision of the estimates of effects. Improvements with antipsychotics need to be balanced against the increased likelihood of dropping out of treatment or experiencing an adverse event. Augmentation of current antidepressant therapy with a second antidepressant, mirtazapine, does not produce a clinically important benefit in reduction of depressive symptoms (high-quality evidence). The evidence regarding the effects of augmenting current antidepressant therapy with buspirone or switching current antidepressant treatment to mianserin is currently insufficient. Further trials are needed to increase the certainty of these findings and to examine long-term effects of treatment, as well as the effectiveness of other pharmacological treatment strategies., (Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Use of supporting materials in cognitive behavioural therapy (CBT) is widely advocated, and homework increases effectiveness. The study aimed to identify materials most frequently used by CBT therapists to support CBT for depression, and those perceived clinically most effective. Questionnaires were sent to 3665 accredited CBT therapists asking about their use of resources commonly described in CBT manuals, and their views on effectiveness. Of 3665 approached by post/email, 994 (27%) responded. Another 33 completed the questionnaire via the study website. 818/1027 (80%) of respondents were accredited practitioners who deliver one-to-one therapy. Symptom measures, lists of problems/goals, activity schedules, behavioural activation diaries/plans, and case formulation worksheets were used "frequently" or "very frequently" by over 85% of respondents. Sleep diaries and computerised CBT were used least. Most resources were used within and between sessions. Activity schedules, behavioural activation diaries/plans, case formulation worksheets, thought records, and resources to support the identification of conditional beliefs were regarded as most effective. Symptom measures, sleep diaries, and computerised/online materials were considered only moderately effective. Therapists use a wide range of materials to support individual CBT. For delivering CBT, technology-enabled approaches should incorporate a range of materials to enable therapists to tailor treatment effectively.

Objective: Cognitive theories suggest people with depression interpret self-referential social information negatively. However, it is unclear whether these biases precede or follow depression. We investigated whether facial expression recognition was associated with depressive symptoms cross-sectionally and longitudinally., Methods: Prospective cohort study of people who had visited UK primary care in the past year reporting depressive symptoms (n = 509). Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9) at four time-points, 2 weeks apart. A computerised task assessed happy and sad facial expression recognition at three time-points (n = 505 at time 1). The unbiased hit rate measured ability to recognise emotions accounting for any general tendency to identify the emotion when it was not present., Results: The sample included the full range of depressive symptom severity, with 45% meeting diagnostic criteria for depression. There was no evidence that happy or sad unbiased hit rates were associated with concurrent or subsequent depressive symptoms. There was weak evidence that, for every additional face incorrectly classified as happy, concurrent PHQ-9 scores reduced by 0.05 of a point (95% CI = -0.10 to 0.002, p = 0.06 after adjustment for confounders). This association was strongest for more ambiguous facial expressions (interaction term p<0.001)., Limitations: This was an observational study with relatively short follow-up (6 weeks) and small changes in depressive symptoms and emotion recognition. Only 7% of invited patients consented to participate., Conclusions: Reduced misclassifications of ambiguous faces as happy could be a state marker of depression, but was not associated with subsequent depressive symptoms. Future research should focus on the interpretation of ambiguous social information., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: We investigated whether depressive symptoms at ages 9-13 years were associated with chronic disabling fatigue (CDF) at age 16 among children in the Avon Longitudinal Study of Parents & Children (ALSPAC) birth cohort., Methods: Depressive symptoms at ages 9, 10, 11, 12, and 13 years were defined as a child- or parent-completed Short Mood and Feelings Questionnaire (SMFQ) score ≥11 (range 0-26). SMFQ score was also analysed as a continuous exposure. Chronic disabling fatigue at 16 was defined as fatigue of ≥6 months' but <5 years' duration which prevented school attendance or activities, for which other causes were not identified, and with a Chalder Fatigue Questionnaire score ≥19. Logistic regression was used with multiple imputation to correct for missing data bias. We performed sensitivity analyses in which children who had CDF and depressive symptoms at age 16 were reclassified as not having CDF., Results: In fully adjusted models using imputed data (N = 13,978), depressive symptoms at ages 9, 11, and 13 years were associated with 2- to 3-fold higher odds of CDF at age 16. Each one-point increase in SMFQ score at ages 9, 10, 11, 12, and 13 years was associated with 6-11% higher odds of CDF at age 16. Depressive symptoms and continuous SMFQ scores at each age were not associated with CDF if the outcome was reclassified to exclude children with comorbid depressive symptoms at age 16., Conclusions: Depressive symptoms at ages 9-13 were associated with chronic disabling fatigue at age 16, but causality is not certain., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Depressive symptoms and inflammation are risk factors for cardiovascular disease (CVD) and mortality. We investigated the combined association of these factors with the prediction of CVD and all-cause mortality in a representative cohort of older men and women., Methods: We measured C-reactive protein (CRP) and depressive symptoms in 5328 men and women aged 52-89 years in the English Longitudinal Study of Ageing. Depressive symptoms were measured using the eight-item Centre for Epidemiological Studies Depression Scale. CRP was analysed from peripheral blood. Mortality was ascertained from national registers and associations with depressive symptoms and inflammation were estimated using Cox proportional hazard models., Results: We identified 112 CVD related deaths out of 420 all-cause deaths in men and 109 CVD related deaths out of 334 all-cause deaths in women over a mean follow-up of 7.7 years. Men with both depressive symptoms and high CRP (3-20 mg/L) had an increased risk of CVD mortality (hazard ratio; 95% confidence interval: 3.89; 2.04-7.44) and all-cause mortality (2.40; 1.65-3.48) after adjusting for age, socioeconomic variables and health behaviours. This considerably exceeds the risks associated with high CRP alone (CVD 2.43; 1.59-3.71, all-cause 1.49; 1.20-1.84). There was no significant increase in mortality risk associated with depressive symptoms alone in men. In women, neither depressive symptoms or inflammation alone or the combination of both significantly predicted CVD or all-cause mortality., Conclusions: The combination of depressive symptoms and increased inflammation confers a considerable increase in CVD mortality risk for men. These effects appear to be independent, suggesting an additive role.

Background: Antidepressants are used both for treating acute episodes and for prophylaxis to prevent future episodes of depression, also called maintenance treatment. This article describes the protocol for a randomised controlled trial (ANTLER: ANTidepressants to prevent reLapse in dEpRession) to investigate the clinical effectiveness and cost-effectiveness in UK primary care of continuing on long-term maintenance antidepressants compared with a placebo in preventing relapse of depression in those who have taken antidepressants for more than 9 months and who are currently well enough to consider stopping maintenance treatment., Methods/design: The ANTLER trial is an individually randomised, double-blind, placebo-controlled trial in which participants are randomised to remain on active medication or to take an identical placebo after a tapering period of 2 months. Eligible participants are those who: are between the ages of 18 and 74 years; have had at least two episodes of depression; and have been taking antidepressants for 9 months or more and are currently taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg but are well enough to consider stopping their medication. The participants will be followed up at 6, 12, 26, 39 and 52 weeks. The primary outcome will be the time in weeks to the beginning of the first episode of depression after randomisation. This will be measured using a retrospective version of the Clinical Interview Schedule-Revised administered at 12, 26, 39 and 52 weeks. Secondary outcomes will include depressive and anxiety symptoms, adverse effects, withdrawal symptoms, emotional processing tasks, quality of life and the resources and costs used. We will also perform a cost-effectiveness analysis based on results of the trial., Discussion: The ANTLER trial findings will inform primary care prescribing practice by providing a valid and generalisable estimate of the clinical effectiveness and cost-effectiveness of long-term maintenance treatment with antidepressants in UK primary care., Trial Registration: Controlled Trials ISRCTN Registry, ISRCTN15969819. Registered on 21 September 2015.

Importance: Paternal depression during the postnatal period has been associated with adverse child outcomes. Family environment has been reported as a pathway for risk transmission from fathers to children. The influence of paternal depression during the postnatal period on offspring depression remains to be clarified., Objective: To investigate the association between paternal depression in the postnatal period and offspring depression and explore potential mediating and moderating factors that influence any association between paternal and offspring depression., Design, Setting, and Participants: This prospective study of a UK community-based birth cohort (the Avon Longitudinal Study of Parents and Children) of parents and their adolescent offspring investigated associations between paternal depression during the postnatal period and offspring depression at age 18 years. We tested a hypothesized moderator (ie, sex) and conducted path analysis to examine hypothesized mediators (ie, depression in the other parent, couple conflict, and paternal involvement and emotional problems, conduct problems, and hyperactivity in offspring at age 3.5 years) of the associations between both paternal and maternal depression and offspring depression. Data collection for the Avon Longitudinal Study of Parents and Children began in 1991 and is ongoing. Data analysis for this study was conducted from June 2015 to September 2018., Exposures: Depression symptoms in fathers at 8 weeks after the birth of their children., Main Outcomes and Measures: Offspring depression symptoms at age 18 years, using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes., Results: A total of 3176 father-offspring pairs were analyzed; of the children, 1764 were girls (55.5%) and 1412 (44.5%) were boys. Paternal mean (SD) age at delivery was 29.6 (9.6) years. The offspring of fathers who had depression during the postnatal period were at increased risk of experiencing depression symptoms at age 18 years (β = 0.053 [95% CI, 0.02-0.09]). The association is mediated by maternal depression at 8 months after birth (β = 0.011 [95% CI, 0.0008-0.02]; 21% [0.011/0.053]) and conduct problems at 42 months after birth (β = 0.004; [95% CI , -0.00004 to 0.009]; 7.5% [0.004/0.053]). Couple conflict and paternal involvement do not mediate this association. The increased risk is seen in girls but not boys (interaction β = 0.095; P = .01)., Conclusions and Relevance: The association between paternal depression in the postnatal period and depression in girls at age 18 years is partially explained by maternal depression. Couple conflict and paternal involvement were not found to play a role in the risk of transmission; this contrasts with the role that couple conflict was found to play in the risk of childhood behavior problems. Conduct problems in childhood appear to be a pathway for risk transmission between paternal depression and subsequent depression in offspring at age 18 years.

Background: Low-grade inflammation is associated with depression, but studies of specific symptoms are relatively scarce. Association between inflammatory markers and specific symptoms may provide insights into potential mechanism of inflammation-related depression. Using longitudinal data, we have tested whether childhood serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels are associated with specific depressive symptoms in early adulthood., Methods: In the ALSPAC birth cohort, serum IL-6 and CRP levels were assessed at age 9 years and 19 depressive symptoms were assessed at age 18 years. We used modified Poisson generalised linear regression with robust error variance to estimate the risk ratio (RR) and 95% confidence interval (95% CI) for each depressive symptom. In addition, we used confirmatory factor analysis to create two continuous latent variables representing somatic/neurovegetative and psychological dimension scores. Structural equation modelling was used to test the associations between IL-6 and these dimension scores., Results: Based on data from 2731 participants, IL-6 was associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances. The adjusted RRs for these symptoms at age 18 years for participants in top, compared with bottom, third of IL-6 at age 9 years were 1.75 (95% CI, 1.13-2.69) for diurnal mood variation, 1.50 (95% CI, 1.11-2.02) for concentration difficulties, 1.31 (95% CI, 1.12-1.54) for fatigue, and 1.24 (95% CI, 1.01-1.52) for sleep disturbances. At dimension level, IL-6 was associated with both somatic/neurovegetative (β = 0.059, SE = 0.024, P = 0.013) and psychological (β = 0.056, SE = 0.023, P = 0.016) scores., Conclusions: Inflammation is associated with specific symptoms of depression. Associations with so-called somatic/neurovegetative symptoms of depression such as fatigue, sleep disturbances and diurnal mood variation indicate that these symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Potentially modifiable risk factors for developing dementia have been identified. However, risk factors for increased mortality in patients with diagnosed dementia are not well understood. Identifying factors that influence prognosis would help clinicians plan care and address unmet needs.AimsTo investigate diagnosed depression and sociodemographic factors as predictors of mortality in patients with dementia in UK secondary clinical care services., Method: We conducted a cohort study of patients with a dementia diagnosis in an electronic health records database in a UK National Health Service mental health trust., Results: In 3374 patients with 10 856 person-years of follow-up, comorbid depression was not associated with mortality (adjusted hazard ratio 0.94; 95% CI 0.71-1.24). Single patients had higher mortality than those who were married (adjusted hazard ratio 1.25; 95% CI 1.03-1.50). Patients of Asian ethnicity had lower mortality rates than White British patients (adjusted hazard ratio 0.50; 95% CI 0.34-0.73)., Conclusions: Clinically diagnosed depression does not increase mortality in patients with dementia. Patients who are single are a potential high-mortality risk group. Lower mortality rates in Asian patients with dementia that have been reported in the USA also apply in the UK.Declaration of interestNone.

Background: To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms., Methods: IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms., Results: Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose-response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68-0.95); that for IL-6 was 1.20 (95% CI, 1.03-1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship., Conclusions: The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people.

Background: There is an association between puberty and depression, but many things remain poorly understood. When assessing puberty in females, most studies combine indicators of breast and pubic hair development which are controlled by different hormonal pathways. The contributions of pubertal timing (age at onset) and pubertal status (stage of development, irrespective of timing) are also poorly understood. We tested the hypothesis that stage of breast development in female adolescents, controlled largely by increased estradiol, would be more strongly associated with depression than pubic hair development which occurs in both males and females, and is controlled by adrenal androgens. We investigated whether this association was independent of pubertal timing., Methods: ROOTS is an ongoing cohort of 1,238 adolescents (54% female) recruited in Cambridgeshire (UK) at age 14.5, and followed-up at ages 16 and 17.5. Depression was assessed using the Mood and Feelings Questionnaire (MFQ) and clinical interview. Breast and pubic hair development were assessed at 14.5, using Tanner rating scales., Results: For each increase in Tanner breast stage at 14.5, depressive symptoms increased by 1.4 MFQ points (95% CI 0.6 to 2.3), irrespective of age at onset. Pubic hair status was only associated with depressive symptoms before adjustment for breast status, and was not associated with depression in males. The same pattern was observed longitudinally, and for depression diagnoses., Limitations: We did not directly measure hormone levels, our findings are observational, and the study had a relatively low response rate., Conclusions: Females at more advanced stages of breast development are at increased risk of depression, even if their age at pubertal onset is not early. Alongside social and psychological factors, hormones controlling breast but not pubic hair development may contribute to increased incidence of female depression during puberty., Competing Interests: The authors have declared that no competing interests exist.

Background: Antidepressants are a first-line treatment for adults with moderate to severe major depression. However, many people prescribed antidepressants for depression don't respond fully to such medication, and little evidence is available to inform the most appropriate 'next step' treatment for such patients, who may be referred to as having treatment-resistant depression (TRD). National Institute for Health and Care Excellence (NICE) guidance suggests that the 'next step' for those who do not respond to antidepressants may include a change in the dose or type of antidepressant medication, the addition of another medication, or the start of psychotherapy. Different types of psychotherapies may be used for TRD; evidence on these treatments is available but has not been collated to date.Along with the sister review of pharmacological therapies for TRD, this review summarises available evidence for the effectiveness of psychotherapies for adults (18 to 74 years) with TRD with the goal of establishing the best 'next step' for this group., Objectives: To assess the effectiveness of psychotherapies for adults with TRD., Search Methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register (until May 2016), along with CENTRAL, MEDLINE, Embase, and PsycINFO via OVID (until 16 May 2017). We also searched the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished and ongoing studies. There were no date or language restrictions., Selection Criteria: We included randomised controlled trials (RCTs) with participants aged 18 to 74 years diagnosed with unipolar depression that had not responded to minimum four weeks of antidepressant treatment at a recommended dose. We excluded studies of drug intolerance. Acceptable diagnoses of unipolar depression were based onthe Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) or earlier versions, International Classification of Diseases (ICD)-10, Feighner criteria, or Research Diagnostic Criteria. We included the following comparisons.1. Any psychological therapy versus antidepressant treatment alone, or another psychological therapy.2. Any psychological therapy given in addition to antidepressant medication versus antidepressant treatment alone, or a psychological therapy alone.Primary outcomes required were change in depressive symptoms and number of dropouts from study or treatment (as a measure of acceptability)., Data Collection and Analysis: We extracted data, assessed risk of bias in duplicate, and resolved disagreements through discussion or consultation with a third person. We conducted random-effects meta-analyses when appropriate. We summarised continuous outcomes using mean differences (MDs) or standardised mean differences (SMDs), and dichotomous outcomes using risk ratios (RRs)., Main Results: We included six trials (n = 698; most participants were women approximately 40 years of age). All studies evaluated psychotherapy plus usual care (with antidepressants) versus usual care (with antidepressants). Three studies addressed the addition of cognitive-behavioural therapy (CBT) to usual care (n = 522), and one each evaluated intensive short-term dynamic psychotherapy (ISTDP) (n = 60), interpersonal therapy (IPT) (n = 34), or group dialectical behavioural therapy (DBT) (n = 19) as the intervention. Most studies were small (except one trial of CBT was large), and all studies were at high risk of detection bias for the main outcome of self-reported depressive symptoms.A random-effects meta-analysis of five trials (n = 575) showed that psychotherapy given in addition to usual care (vs usual care alone) produced improvement in self-reported depressive symptoms (MD -4.07 points, 95% confidence interval (CI) -7.07 to -1.07 on the Beck Depression Inventory (BDI) scale) over the short term (up to six months). Effects were similar when data from all six studies were combined for self-reported depressive symptoms (SMD -0.40, 95% CI -0.65 to -0.14; n = 635). The quality of this evidence was moderate. Similar moderate-quality evidence of benefit was seen on the Patient Health Questionnaire-9 Scale (PHQ-9) from two studies (MD -4.66, 95% CI 8.72 to -0.59; n = 482) and on the Hamilton Depression Rating Scale (HAMD) from four studies (MD -3.28, 95% CI -5.71 to -0.85; n = 193).High-quality evidence shows no differential dropout (a measure of acceptability) between intervention and comparator groups over the short term (RR 0.85, 95% CI 0.58 to 1.24; six studies; n = 698).Moderate-quality evidence for remission from six studies (RR 1.92, 95% CI 1.46 to 2.52; n = 635) and low-quality evidence for response from four studies (RR 1.80, 95% CI 1.2 to 2.7; n = 556) indicate that psychotherapy was beneficial as an adjunct to usual care over the short term.With the addition of CBT, low-quality evidence suggests lower depression scores on the BDI scale over the medium term (12 months) (RR -3.40, 95% CI -7.21 to 0.40; two studies; n = 475) and over the long term (46 months) (RR -1.90, 95% CI -3.22 to -0.58; one study; n = 248). Moderate-quality evidence for adjunctive CBT suggests no difference in acceptability (dropout) over the medium term (RR 0.98, 95% CI 0.66 to 1.47; two studies; n = 549) and lower dropout over long term (RR 0.80, 95% CI 0.66 to 0.97; one study; n = 248).Two studies reported serious adverse events (one suicide, two hospitalisations, and two exacerbations of depression) in 4.2% of the total sample, which occurred only in the usual care group (no events in the intervention group).An economic analysis (conducted as part of an included study) from the UK healthcare perspective (National Health Service (NHS)) revealed that adjunctive CBT was cost-effective over nearly four years., Authors' Conclusions: Moderate-quality evidence shows that psychotherapy added to usual care (with antidepressants) is beneficial for depressive symptoms and for response and remission rates over the short term for patients with TRD. Medium- and long-term effects seem similarly beneficial, although most evidence was derived from a single large trial. Psychotherapy added to usual care seems as acceptable as usual care alone.Further evidence is needed on the effectiveness of different types of psychotherapies for patients with TRD. No evidence currently shows whether switching to a psychotherapy is more beneficial for this patient group than continuing an antidepressant medication regimen. Addressing this evidence gap is an important goal for researchers.