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BACKGROUND: Internet-cognitive behavioural therapy (iCBT) for depression can include multiple components. This study explored depressive symptom improvement prognostic factors (PFs) and effect modifiers (EMs) for five common iCBT components including behavioural activation, cognitive restructuring, problem solving, self-monitoring, and assertion training. METHODS: We used data from a factorial trial of iCBT for subthreshold depression among Japanese university students (N=1093). The primary outcome was the change in PHQ-9 scores at 8weeks from baseline. Interactions between each component and various baseline characteristics were estimated using a mixed-effects model for repeated measures. We calculated multiplicity-adjusted p-values at 5% false discovery rate using the Benjamini-Hochberg procedure. RESULTS: After multiplicity adjustment, the baseline PHQ-9 total score emerged as a PF and exercise habits as an EM for self-monitoring (adjusted p-values

BackgroundInternet-based cognitive-behavioural therapy (iCBT) is effective for subthreshold depression. However, which skills provided in iCBT packages are more effective than others is unclear. Such knowledge can inform construction of more effective and efficient iCBT programmes.ObjectiveTo examine the efficacy of five components of iCBT for subthreshold depression.MethodsWe conducted an factorial trial using a smartphone app, randomly allocating presence or absence of five iCBT skills including self-monitoring, behavioural activation (BA), cognitive restructuring (CR), assertiveness training (AT) and problem-solving. Participants were university students with subthreshold depression. The primary outcome was the change on the Patient Health Questionnaire-9 (PHQ-9) from baseline to week 8. Secondary outcomes included changes in CBT skills.FindingsWe randomised a total of 1093 participants. In all groups, participants had a significant PHQ-9 reduction from baseline to week 8. Depression reduction was not significantly different between presence or absence of any component, with corresponding standardised mean differences (negative values indicate specific efficacy in favour of the component) ranging between −0.04 (95% CI −0.16 to 0.08) for BA and 0.06 (95% CI −0.06 to 0.18) for AT. Specific CBT skill improvements were noted for CR and AT but not for the others.ConclusionsThere was significant reduction in depression for all participants regardless of the presence and absence of the examined iCBT components.Clinical implicationWe cannot yet make evidence-based recommendations for specific iCBT components. We suggest that future iCBT optimisation research should scrutinise the amount and structure of components to examine.Trial registration numberUMINCTR-000031307.

BackgroundDietary interventions did not prevent depression onset nor reduced depressive symptoms in a large multi-center randomized controlled depression prevention study (MooDFOOD) involving overweight adults with subsyndromal depressive symptoms. We conducted follow-up analyses to investigate whether dietary interventions differ in their effects on depressive symptom profiles (mood/cognition; somatic; atypical, energy-related).MethodsBaseline, 3-, 6-, and 12-month follow-up data from MooDFOOD were used (n = 933). Participants received (1) placebo supplements, (2) food-related behavioral activation (F-BA) therapy with placebo supplements, (3) multi-nutrient supplements (omega-3 fatty acids and a multi-vitamin), or (4) F-BA therapy with multi-nutrient supplements. Depressive symptom profiles were based on the Inventory of Depressive Symptomatology.ResultsF-BA therapy was significantly associated with decreased severity of the somatic (B = −0.03, p = 0.014, d = −0.10) and energy-related (B = −0.08, p = 0.001, d = −0.13), but not with the mood/cognition symptom profile, whereas multi-nutrient supplementation was significantly associated with increased severity of the mood/cognition (B = 0.05, p = 0.022, d = 0.09) and the energy-related (B = 0.07, p = 0.002, d = 0.12) but not with the somatic symptom profile.ConclusionsDifferentiating depressive symptom profiles indicated that food-related behavioral interventions are most beneficial to alleviate somatic symptoms and symptoms of the atypical, energy-related profile linked to an immuno-metabolic form of depression, although effect sizes were small. Multi-nutrient supplements are not indicated to reduce depressive symptom profiles. These findings show that attention to clinical heterogeneity in depression is of importance when studying dietary interventions.

The present case series reports the preliminary test of a rumination-focused cognitive-behavioral therapy (RFCBT) self-help program to reduce depressive rumination among Japanese female undergraduates. A workbook-type self-help program based on RFCBT was implemented with 39 participants showing a high tendency toward rumination/worry. Data from 30 participants who completed one or more modules were analyzed quantitatively. The results showed significant reductions of rumination, worry, and anxiety at post-intervention. Further, semistructured interviews were conducted with 13 participants who completed the program, and verbatim data were examined using content analysis. The contents found to be useful and difficult differed for each participant and each module. Based on these results, the future implementation and dissemination of RFCBT is discussed.

Depression is highly recurrent, even following successful pharmacological and/or psychological intervention. We aimed to develop clinical prediction models to inform adults with recurrent depression choosing between antidepressant medication (ADM) maintenance or switching to mindfulness-based cognitive therapy (MBCT). Using previously published data ( N = 424), we constructed prognostic models using elastic-net regression that combined demographic, clinical, and psychological factors to predict relapse at 24 months under ADM or MBCT. Only the ADM model (discrimination performance: area under the curve [AUC] = .68) predicted relapse better than baseline depression severity (AUC = .54; one-tailed DeLong’s test: z = 2.8, p = .003). Individuals with the poorest ADM prognoses who switched to MBCT had better outcomes compared with individuals who maintained ADM (48% vs. 70% relapse, respectively; superior survival times, z = −2.7, p = .008). For individuals with moderate to good ADM prognoses, both treatments resulted in similar likelihood of relapse. If replicated, the results suggest that predictive modeling can inform clinical decision-making around relapse prevention in recurrent depression.

Adolescents frequently engage in high-risk behaviours (HRB) following childhood sexual abuse (CSA). Aberrant reward processes are implicated in HRB, and their underlying fronto-striatal networks are vulnerable to neurodevelopmental changes during adversity representing a promising candidate for understanding links between CSA and HRB. We examined whether fronto-striatal responses during reward anticipation and feedback (i) are altered in depressed adolescents with CSA compared to depressed, non-abused peers and (ii) moderate the relationship between CSA and HRB irrespective of depression. Forty-eight female adolescents {14 with CSA and depression [CSA + major depressive disorder (MDD)]; 17 with MDD but no CSA (MDD); 17 healthy, non-abused controls} completed a monetary reward task during functional magnetic resonance imaging. No differences in fronto-striatal response to reward emerged between CSA + MDD and MDD. Critically, high left nucleus accumbens activation during reward anticipation was associated with greater HRB in CSA + MDD compared to MDD and controls. Low left putamen activation during reward feedback was associated with the absence of HRB in CSA + MDD compared to MDD. Striatal reward responses appear to play a key role in HRB for adolescents with CSA irrespective of depression, providing initial support for a CSA ecophenotype. Such information is pivotal to identify at-risk youth and prevent HRB in adolescents after CSA.

This trial introduces a novel transdiagnostic intervention (Shaping Healthy Minds) designed to address the gap in effective interventions for people with complex and comorbid presentations including anxiety, disturbed mood, and trauma sequelae. Shaping Healthy Minds is a modular intervention which synthesises several evidence-based treatment techniques, allowing for standardised, yet flexible, treatment delivery. We conducted a patient-level two-arm randomised controlled trial (HARMONIC) that compared Shaping Healthy Minds to psychological treatment-as-usual (PTAU) for individuals aged >18 years (n = 42). Participants met criteria for at least two comorbid mood, anxiety, obsessive-compulsive or trauma/stressor disorder diagnoses and were recruited from outpatient psychological services within the UK National Health Service (NHS). This early phase trial aimed to estimate the efficacy, feasibility, and acceptability of the transdiagnostic intervention. We obtained estimates of likely effect size and acquired basic demographic, cognitive and behavioural data to assess potential mediators and moderators of outcome in preparation for a later phase fully-powered efficacy trial. Co-primary outcomes were self-reported depression and anxiety symptoms, disability and functional impairment; and the trial provided point estimates of efficacy for Shaping Healthy Minds versus Psychological TAU with moderate effect sizes in favour of Shaping Healthy Minds at post-treatment (Cohen’s d estimates ranging from 0.60-0.92) and at 3-month follow-up (Cohen’s d 0.41-0.48). Secondary outcomes included number of diagnoses and changes in transdiagnostic processes. The project has demonstrated that a full trial is feasible, and that the Shaping Healthy Minds treatment approach appears likely to be efficacious compared to PTAU. The trial procedures were approved by the Health Research Authority of the NHS of the UK (East of England, Reference: 16/EE/0095). The results of this feasibility trial will inform future large-scale trials of psychological interventions for co-occurring mood, anxiety, and stressor-related disorders.Trial registration NCT03143634.

BACKGROUND Rumination and worry are common risk factors of depression and anxiety. Internet-based transdiagnostic interventions targeting individuals with these specific risks may be an effective way to prevent depression and anxiety. OBJECTIVE This study developed and compared the efficacy of two Internet-based transdiagnostic interventions with online guidance to an Internet-based psychoeducation control group in reducing risks and symptoms of depression and anxiety. METHODS This three-arm randomized controlled trial compared Internet-based rumination-focused cognitive behavioral therapy (RFCBT), mindfulness-based intervention (MBI), and psychoeducation control (EDU). A total of 256 participants were randomised into one of the three courses and received a 6-module program. Participants’ level of rumination, worry, depressive and anxiety symptoms were assessed at post-intervention (6 weeks), at 3-month and 9-month follow up. Efficacy was tested using Linear Mixed Model analysis. RESULTS Results showed similar levels of improvement on all outcomes across the three conditions. Change in rumination differed comparing RFCBT and MBI, where a fluctuation on rumination was noted at 3-month follow up among participants in RFCBT and an absence of long-term effect on was noted among participants in MBI at 9-month follow up. CONCLUSIONS All three conditions showed similar reduction in risks and symptoms implied that the two active interventions were not superior to psychoeducation control. The high attrition at follow-ups suggested the need for caution concerning the findings. Future studies should tease apart placebo effect and identify ways to improve adherence. CLINICALTRIAL Chinese Clinical Trial Registry (Trial no: ChiCTR-IOR-15006470)

Objective To undertake meta-analysis and compare treatment effects estimated by the intention-to-treat (ITT) method and per-protocol (PP) method in randomized controlled trials (RCTs). PP excludes trial participants who are non-adherent to trial protocol in terms of eligibility, interventions, or outcome assessment. Study design and setting Five high impact journals were searched for all RCTs published between July 2017 to June 2019. Primary outcome was a pooled estimate that quantified the difference between the treatment effects estimated by the two methods. Results are presented as ratio of odds ratios (ROR). Meta-regression was used to explore the association between level of trial protocol non-adherence and treatment effect. Sensitivity analyses compared results with varying within-study correlations and across various study characteristics. Results Random-effects meta-analysis (N = 156) showed that PP estimates were on average 2% greater compared to the ITT estimates (ROR: 1.02, 95% CI: 1.00–1.04, P = 0.03). The divergence further increased with higher degree of protocol non-adherence. Sensitivity analyses reassured consistent results with various within-study correlations and across various study characteristics. Conclusion There was evidence of larger treatment effect with PP compared to ITT analysis. PP analysis should not be used to assess the impact of protocol non-adherence in RCTs. Instead, in addition to ITT, investigators should consider randomization based casual method such as Complier Average Causal Effect (CACE).

Individuals with depression typically remember their past in a generalised manner, at the cost of retrieving specific event memories. This may impair engagement with cognitive behavioural therapy (CBT) tasks that use concrete episodic information to challenge maladaptive beliefs, potentially limiting their therapeutic benefit. Study 1 demonstrated that an episodic specificity induction increased detail and specificity of autobiographical memory in people with major depression, relative to control conditions (N=88). We therefore examined whether the induction enhanced the efficacy of CBT tasks that depend on episodic memory – cognitive reappraisal (Study 2, N=30), evidence gathering (Study 2, N=30), and planning behavioural experiments (Study 3, N=30). Across all three tasks, there were no significant differences in emotion- or belief-change between the specificity and control conditions. Although the induction temporarily enhanced specificity in depressed individuals, it did not significantly boost the efficacy of CBT tasks theorised to benefit from the use of specific mnemonic information.

This research has been conducted using the UK Biobank resource under application number 9072. Copyright © The Author(s) 2021. Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one-and two-sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß:-0.15, 95%CI:-0.26,-0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being. Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079 to J.O., F.C. and J.T.); Wellcome Senior Research Fellowship (WT220390 to R.M.F.). Diabetes UK RD Lawrence fellowship (17/0005594 to H.Y.).

In this study, we tested potential mediators that may explain change in depressive symptoms following exposure to a food-related behavioral activation intervention (F-BA). These included behavioral activation, avoidance and rumination, eating styles, body mass index, and dietary behavior at baseline and 3-month and 12-month follow-up. The trial used a community sample of 1,025 overweight adults with elevated depressive symptoms without current major depression. Participants were randomly assigned to one of four trial arms: either daily nutritional supplements (vs. placebo) alone or in combination with F-BA (vs. no F-BA) over 12 months. Although F-BA did not significantly reduce depressive symptoms (standardized regression coefficient [ b] = −0.223, SE = 0.129; p = .084), significant mediators included emotional eating ( b = −0.028, SE = 0.014; p = .042) and uncontrolled eating ( b = −0.039, SE = 0.016; p = .013), suggesting that learning adaptive responses to emotional and food cues may underlie effects of F-BA on depressive symptoms.

Background: Repetitive negative thinking (RNT) is considered to be an important transdiagnostic factor in the onset, course and recurrence of both depressive and anxiety disorders. This study aimed to investigate whether an add-on group intervention ‘Drop it’, compared to treatment as usual, would improve RNT, anxiety and depressive symptoms, as well as quality of life and self-esteem of patients with Major Depressive Disorder (MDD) and/or Generalized Anxiety Disorder (GAD). Methods: Eighty patients were randomly allocated to 8 sessions of group intervention (n = 45) or a delayed treatment control group (n = 35). Both conditions continued their ongoing mental health care. Assessments took place before randomization, 12 weeks later (after group intervention) and at 3- and 9- months follow-up. Results: Although all outcomes improved after the intervention, only the uncontrollability of rumination, worrying, distancing oneself from one’s thoughts, and quality of life remained statistically significant after Bonferroni correction compared to the delayed treatment control group. Conclusions: Group intervention improves RNT and quality of life of patients treated for MDD and/or GAD. Improvements remain stable until 9 months after treatment. Limitations of the study included the small sample size, the lack of a long-term follow-up in the delayed treatment control group and the inclusion of highly educated patients with mainly high comorbid generalized anxiety disorder and depression.

A reciprocal relationship between repetitive negative thinking (RNT) and negative affect (NA) has been found in various types of psychopathology. Recent studies have suggested that the magnitude of this association can vary across time and individuals, which may inform future psychopathology. Here, we explored how these dynamics and interplays are manifested in student and general populations using a statistical clustering algorithm. Across three experience-sampling data sets, our clustering analyses consistently identified two groups of individuals; one group had a higher bidirectional association between RNT and NA (and also higher inertia) than the other group. Furthermore, a prospective analysis revealed that the group with the higher bidirectional association is at risk of developing depressive symptoms during the 3-month follow-up period if they had experienced high levels of NA over the experience-sampling phase. These findings suggest that the dysfunctional affective and cognitive dynamics would be a promising target of preventive intervention.

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.

Anger dysregulation is part of a broad range of clinical disorders, and as a dynamic risk factor for aggression anger is highly relevant in clinical populations. Problems of anger and reactive aggression are trans-diagnostic and treatments should target the mechanisms involved in problematic anger across disorders. There is empirical evidence that anger rumination is associated with anger as well as aggression. Because rumination-focused CBT (RfCBT) has shown that reduction in rumination seems to be associated with transdiagnostic reductions in symptoms, the present study aimed at extending the applicability of the RfCBT model to target problematic anger in a case of schizotypal personality disorder (SPD). The current study was a clinical case study with a patient suffering from problematic anger and anger rumination, and diagnosed with schizotypal personality disorder (SPD) receiving 25 sessions of rumination-focused CBT (RfCBT) for problematic anger. The primary focus was on anger and anger rumination, which was reduced during therapy, and maintained in the 3 months follow up. Results on the measures of repetitive negative thinking also showed a decrease, however symptoms of depression and anxiety had increased from pre- to post treatment. RfCBT can be applied to a case of SPD with problematic anger, thereby showing proof of concept for a transdiagnostic use of RfCBT and opening up for future research in this area. The applicability of RfCBT to anger problems among patients diagnosed with SPD needs to be replicated in a larger sample of patients diagnosed with SPD/problematic anger and anger rumination.

ObjectiveDepressed 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.MethodsIndividual 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.ResultsSocial 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%).ConclusionsOverall, 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.

RationaleRumination is a repetitive, negative, self-focused thinking style associated with various forms of psychopathology. Recent studies suggest that rumination increases craving for alcohol and predicts harmful drinking and alcohol-related problems. However, the acute effects of alcohol on rumination have not been previously studied. It is proposed that alcohol may reduce ruminative thinking through decreasing negative mood.ObjectivesIn the present study, we aimed to test the previously unexplored effects of acute alcohol consumption on rumination in a hazardous drinking population.MethodsWe conducted a randomised placebo-controlled laboratory study to examine the effect of low (0.4 g kg−1) and high doses (0.8 g kg−1) of alcohol on state rumination compared to placebo. Participants completed a rumination induction task prior to receiving drinks. We then measured state rumination and mood at repeated time points; 30 min, 60 min and 90 min post-drinks consumption.ResultsWe found a significant decrease in state rumination in the low-dose alcohol group compared to placebo at 30 min post-alcohol consumption, but no difference was observed between the high-dose alcohol and placebo groups. Mediation analysis provided evidence for an indirect effect of alcohol on state rumination through concurrent changes in negative mood.ConclusionsThese findings suggest that acute alcohol consumption can regulate negative mood and concurrently rumination, providing preliminary evidence for the role of rumination in alcohol use disorders. Rumination may be a treatment target in alcohol use disorders.

Background There is ambiguity on how omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are associated with depression, and what the temporality of the association might be. The present study aimed to examine whether (intervention-induced changes in) n-3 PUFA levels were associated with (changes in) depressive symptoms. Methods Baseline, 6- and 12-month follow-up data on 682 overweight and subclinically depressed persons from four European countries that participated in the MooDFOOD depression prevention randomized controlled trial were used. Participants were allocated to four intervention groups: (a) placebos, (b) placebos and food-related behavioral activation therapy (F-BA), (c) multinutrient supplements (fish oil and multivitamin), and (d) multinutrient supplements and F-BA. Depressive symptoms were measured using the inventory of depressive symptomatology. PUFA levels (mu mol/L) were measured using gas chromatography. Analyses were adjusted for sociodemographics, lifestyle, and somatic health. Results Increases in n-3 PUFA, docosahexaenoic acid, and eicosapentaenoic acid levels over time were significantly larger in the supplement groups than in placebo groups. Change in PUFA levels was not significantly associated with the change in depressive symptoms (beta = .002, SE = 0.003,p = .39;beta = .003, SE = 0.005,p = .64;beta = .005, SE = 0.005,p = .29;beta = -.0002, SE = 0.0004,p = .69). Baseline PUFA levels did not modify the intervention effects on depressive symptoms. Conclusions In overweight and subclinical depressed persons, multinutrient supplements led to significant increases in n-3 PUFA levels over time, which were not associated with changes in depressive symptoms. Multinutrient supplements do not seem to be an effective preventive strategy in lowering depressive symptoms over time in these at-risk groups., European Union FP7 MooDFOOD project, Grant/Award Number: 613598; National Institute for Health Research (NIHR), through the Primary Care Research Network and the NIHR Exeter Clinical Research Facility

Objective: Depression and obesity are bi-directionally related, eating styles and diet quality are two important factors associated with both. It remains uncertain if and how these two factors can be modified. Therefore the current study aims to investigate whether food-related behavioral activation therapy (F-BA), targeting mood, dietary habits and food related behavior, can improve eating styles, and diet quality and reduce body weight in adults with overweight or obesity and subsyndromal depressive symptoms. Methods: Data were derived from the MooDFOOD prevention trial, a 2x2 factorial RCT investigating the effect of nutritional strategies on prevention of depression. Changes in emotional, uncontrolled, and cognitive restrained eating (Three Factor Eating Questionnaire Revised), Mediterranean Diet Score (MDS), and body weight were analyzed among 1025 adults who either received F-BA or no intervention for 12 months. Intervention effect was tested by longitudinal analysis of covariance using mixed model analysis. Results: The F-BA group showed a small decrease in emotional (β=-5.68, p

Objective Depression is common in people who have experienced recent Acute Coronary Syndrome (ACS), and predicts worse medical outcomes. Mechanisms underpinning the development of depression and its association with poor medical outcomes are unclear however. The aim of this study was to investigate the role of perseverative negative thinking (e.g. worry and rumination) in predicting depression in people with recent ACS. Methods Adults attending specialist inpatient and outpatient cardiology services who had recently experienced ACS were invited to participate in this observational prospective cohort study. Questionnaire assessments were completed within 6 months of index ACS (baseline), then 2 months and 6 months later. Results 169 participants (131 male (78%), median age 68 (±16) years) completed baseline questionnaires, and 111 completed follow-ups. After controlling for the effects of key covariates, baseline rumination was a significant predictor of depression at 6 months, accounting for 2% of the variance in depression. This association was partially mediated by poor problem-solving ability and lack of social support. Neither worry nor rumination at baseline were significant predictors of quality of life at 6 months. Conclusions Rumination is a significant independent predictor of depression, and this association may be partially explained by deficits in problem-solving ability and reduced social support. Both rumination and problem solving may provide useful targets for the development of evidence-based interventions to reduce depression among people with coronary heart disease.

BackgroundDepression 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.MethodIndividual 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.ResultsItem-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.ConclusionThe 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.

BackgroundThis study aimed to investigate general factors associated with prognosis regardless of the type of treatment received, for adults with depression in primary care.MethodsWe 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.ResultsTwelve (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.ConclusionsWhen 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.

Background Adolescent-onset depression often results in a chronic and recurrent course, and is associated with worse outcomes relative to adult-onset depression. Targeting habitual depressive rumination, a specific known risk factor for relapse, may improve clinical outcomes for adolescents who have experienced a depressive episode. Randomized controlled trials (RCTs) thus far have demonstrated that rumination-focused cognitive behavioral therapy (RFCBT) reduces depressive symptoms and relapse rates in patients with residual depression and adolescents and young adults with elevated rumination. This was also observed in a pilot RCT of adolescents at risk for depressive relapse. Rumination can be measured at the self-report, behavioral, and neural levels- using patterns of connectivity between the Default Mode Network (DMN) and Cognitive Control Network (CCN). Disrupted connectivity is a putative important mechanism for understanding reduced rumination via RFCBT. A feasibility trial in adolescents found that reductions in connectivity between DMN and CCN regions following RFCBT were correlated with change in rumination and depressive symptoms. Method This is a phase III two-arm, two-stage, RCT of depression prevention. The trial tests whether RFCBT reduces identified risk factors for depressive relapse (rumination, patterns of neural connectivity, and depressive symptoms) in adolescents with partially or fully remitted depression and elevated rumination. In the first stage, RFCBT is compared to treatment as usual within the community. In the second stage, the comparator condition is relaxation therapy. Primary outcomes will be (a) reductions in depressive rumination, assessed using the Rumination Response Scale, and (b) reductions in resting state functional magnetic resonance imaging connectivity of DMN (posterior cingulate cortex) to CCN (inferior frontal gyrus), at 16 weeks post-randomization. Secondary outcomes include change in symptoms of depression following treatment, recurrence of depression over 12 months post-intervention period, and whether engagement with therapy homework (as a dose measure) is related to changes in the primary outcomes. Discussion RFCBT will be evaluated as a putative preventive therapy to reduce the risk of depressive relapse in adolescents, and influence the identified self-report, behavioral, and neural mechanisms of change. Understanding mechanisms that underlie change in rumination is necessary to improve and further disseminate preventive interventions. Trial registration ClinicalTrials.gov Identifier: NCT03859297, registered 01 March 2019.

Background: Major depression disorder (MDD)11 Abbreviations: BMI: Body mass index; MDD: Major depressive disorder; WHR: wait-to-hip-ratio and obesity are among the most common public health problems. The majority of epidemiological studies demonstrated a strong relationship between sociodemographic factors like age and socioeconomic status and depression. Also, a bidirectional link between depression and obesity is discussed. However, differences regarding sociodemographic factors and obesity between participants with and without lifetime MDD might occur, but potentially not in all individuals. This study intends to contribute to this discussion by investigating whether or not sociodemographic factors, chronic illness status, and overweight differ between individuals with and without lifetime MDD. Methods: In the MooDFOOD depression prevention trial, 1025 overweight or obese participants with subsyndromal symptoms of depression were recruited. Lifetime history of MDD, number of lifetime MDD episodes, sociodemographic data, and chronic illness were assessed via clinical interview, also standardized anthropometric measures (body mass index [BMI], waist-to-hip ratio [WHR]). Results: A lifetime MDD diagnosis was present in 33.5% of the sample. Individuals with lifetime MDD and individuals who never suffered from MDD did not differ regarding sex, age, marital status, educational level, employment status, and income. Further, there were no significant differences in BMI, WHR, and number of chronic illnesses between participants with and without lifetime MDD. Limitations: The cross-sectional nature of the data prohibited causal inferences. Conclusion: Sociodemographic variables, chronic illness status and anthropometric measures seem not to be related to the status of having suffered from MDD in the past vs. not having suffered from MDD in people who are currently overweight or obese.

Objective:\ud To undertake a methodological review of statistical methods used in randomized controlled trials (RCTs) for handling intervention nonadherence.\ud \ud Study Design and Setting:\ud Bibliographic databases were searched using predefined search terms.\ud \ud Results:\ud A substantive number of identified studies (56%) were excluded as they only used naive per protocol analysis for handling nonadherence. Our review included 58 articles published between 1991 and 2015. A total of 88 methodological applications were made by these studies. The two most used methods were complier average causal effect (56%) and instrumental variable (23%) predominantly with the use of maximum likelihood (ML) estimators. These alternative applications typically produced treatment effects greater than the intention-to-treat effect but as their standard errors were larger there was no statistical difference between the methods.\ud \ud Conclusion:\ud A substantive proportion of RCTs rely on naive per protocol for handling nonadherence. Recent years have seen an increasing number of applications of more appropriate statistical methods, in particular complier average causal effect and instrumental variable methods. However, these later methods rely on strong underlying assumptions that may be vulnerable to violation. More empirical studies are needed that directly compare the usability and performance of different statistical methods for nonadherence in RCTs.

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.

Repetitive negative thinking (RNT) is a proximal risk factor implicated in the onset and maintenance of common mental health problems such as depression and anxiety. Adolescence may be a key developmental window in which to target RNT and prevent the emergence of such disorders. Impairments in updating the contents of working memory are hypothesised to causally contribute to RNT, and some theorists have suggested these difficulties may be specific to the manipulation of negative information. The present study compared the effects of computerised adaptive working memory updating training (in which the task becomes more difficult as performance improves) to a non-adaptive control task in reducing levels of RNT. 124 healthy young people were randomised to 20 sessions of (i) working memory updating training using neutral stimuli, (ii) working memory updating training using negative stimuli, or (iii) non-adaptive working memory updating training. Adaptive working memory updating training using neutral, but not negative, stimuli resulted in significant improvements to working memory updating for negative material, as assessed using an unpractised task, and significant reductions in susceptibility to state RNT. These findings demonstrate proof-of-concept that working memory updating training has the potential to reduce susceptibility to episodes of state RNT., Highlights • 124 young people participated in a novel working memory updating training. • Training using neutral, but not negative, stimuli improved working memory updating. • Training using neutral stimuli also reduced repetitive negative thinking. • Working memory updating causally influences repetitive negative thought. • Targeted working memory updating training may be a valuable preventive approach.

Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preference on mental health outcomes, including anxiety, depression and general wellbeing and test the hypothesis that more misaligned individuals have poorer mental health and wellbeing using an actigraphy-based measure of circadian misalignment. Multiple Mendelian Randomisation (MR) approaches were used to test causal pathways between diurnal preference and seven well-validated mental health and wellbeing outcomes in up to 451,025 individuals. In addition, observational analyses tested the association between a novel, objective measure of behavioural misalignment (Composite Phase Deviation, CPD) and seven mental health and wellbeing outcomes. Using genetic instruments identified in the largest GWAS for diurnal preference, we provide robust evidence that early diurnal preference is protective for depression and improves wellbeing. For example, using one-sample MR, a twofold higher genetic liability of morningness was associated with lower odds of depressive symptoms (OR: 0.92, 95% CI: 0.88, 0.97). It is possible that behavioural factors including circadian misalignment may contribute in the chronotype depression relationship, but further work is needed to confirm these findings.

Background: Meta-analysis of observational studies concluded that soft drinks may increase the risk of depression, while high consumption of coffee and tea may reduce the risk. Objectives were to explore the associations between the consumption of soft drinks, coffee or tea and: (1) a history of major depressive disorder (MDD) and (2) the severity of depressive symptoms clusters (mood, cognitive and somatic/vegetative symptoms). Methods: Cross-sectional and longitudinal analysis based on baseline and 12-month-follow-up data collected from four countries participating in the European MooDFOOD prevention trial. In total, 941 overweight adults with subsyndromal depressive symptoms aged 18 to 75 years were analyzed. History of MDD, depressive symptoms and beverages intake were assessed. Results: Sugar-sweetened soft drinks were positively related to MDD history rates whereas soft drinks with non-nutritive sweeteners were inversely related for the high vs. low categories of intake. Longitudinal analysis showed no significant associations between beverages and mood, cognitive and somatic/vegetative clusters. Conclusion: Our findings point toward a relationship between soft drinks and past MDD diagnoses depending on how they are sweetened while we found no association with coffee and tea. No significant effects were found between any studied beverages and the depressive symptoms clusters in a sample of overweight adults., Funding for this paper was provided by the European Union FP7 MooDFOOD Project Multi-country collaborative project on the role of diet, food-related behaviour, and obesity in the prevention of depression (grant agreement no. 613598). This work is supported in the UK by the National Institute for Health Research (NIHR), through the Primary Care Research Network, and the NIHR Exeter Clinical Research Facility. Funding sponsors did not participate in the study design; collection, management, analysis, and interpretation of data; or writing of the report. They did not participate in the decision to submit the report for publication.

Depression is highly recurrent, even following successful pharmacological and/or psychological intervention. We aimed to develop clinical prediction models to inform adults with recurrent depression choosing between antidepressant medication (ADM) maintenance or switching to Mindfulness-Based Cognitive Therapy (MBCT). Using data from the PREVENT trial (N=424), we constructed prognostic models using elastic net regression that combined demographic, clinical and psychological factors to predict relapse at 24 months under ADM or MBCT. Only the ADM model (discrimination performance: AUC=.68) predicted relapse better than baseline depression severity (AUC=.54; one-tailed DeLong’s test: z=2.8, p=.003). Individuals with the poorest ADM prognoses who switched to MBCT had better outcomes compared to those who maintained ADM (48% vs. 70% relapse, respectively; superior survival times [z=−2.7, p=.008]). For individuals with moderate-to-good ADM prognosis, both treatments resulted in similar likelihood of relapse. If replicated, the results suggest that predictive modeling can inform clinical decision-making around relapse prevention in recurrent depression.

OBJECTIVES: Rumination involves a repetitive, passive focus on one’s thoughts and feelings and has been hypothesized as a mechanism contributing to multiple psychopathologies. The current investigation explores secondary outcomes from a pilot study to examine whether rumination-focused cognitive behavior therapy (RFCBT) alleviates symptoms of anxiety, increases behavioral activation, or increases global functioning among adolescents with a history of Major Depressive Disorder (MDD). METHODS: Thirty-three adolescents were randomized to receive either RFCBT (n = 17) or assessment only (AO; n = 16) over the course of eight weeks. Mixed effects regression models were used to conduct intent-to-treat (ITT) analyses. RESULTS: The quadratic interaction for group-by-time-by-time was significant for anxiety. Adolescents in the RFCBT group experienced a significant decrease in anxiety across the first six weeks of intervention (F = 7.01, df = 108.49, p = .009). The group-by-time interaction was significant for the behavioral activation outcome (F = 4.28, df = 25.60, p = .049) with youth randomized to RFCBT demonstrating increasing activation compared to AO. Global functioning did not significantly differ between groups (F = .40, df = 1, p > .05). CONCLUSIONS: Preliminary evidence suggests that RFCBT may hold promise as an intervention that alleviates both depressive and anxiety symptoms when comorbid.

Background: There is evidence that depressive symptom severity is associated with prognosis but existing studies have usually been for people on a single treatment so we lack evidence for this effect independent of treatment. There are other factors that we will call ‘disorder severity’ such as duration and comorbidity that have been reported as associated with prognosis, but current evidence does not indicate if these associations are independent of treatment and symptom severity. Methods: Medline, Embase, PsycINFO and Cochrane Central were searched from inception to 20th March 2019 for randomised controlled trials (RCTs) of adults seeking treatment for depression from their general practitioners, that used the Revised Clinical Interview Schedule (CIS-R) so that there was uniformity in the measurement of disorder severity factors. Individual participant data were gathered from 12 RCTs. Two-stage random-effects meta-analyses were undertaken calculating effect estimates within each study and then pooling across these to ascertain the independent association between each potential prognostic factor and depressive symptoms at 3-4 months post-baseline, remission and depressive symptoms at 6-8 months post-baseline. Risk of bias was calculated using QUIPS and quality was assessed using GRADE. Findings: Baseline depressive symptom severity was strongly associated with prognosis independent of treatment; there was a 27∙5%(95%CI: 25∙0 to 30∙1) difference in depressive symptoms at 3-4 months per one standard deviation increase in baseline score, equivalent to about eight Beck Depression Inventory points or five PHQ-9 points. The duration of anxiety, duration of depression, comorbid panic disorder, and a history of antidepressant treatment were also associated with prognosis independent of depressive symptom severity, though the association with antidepressant treatment was less robust. For participants with all four of these factors, there was a difference of 39∙9%(95%CI: 12∙6 to 74∙0) in their score at 3-4 months. Risk of bias was low in all studies, quality was high and heterogeneity was within acceptable limits for all but two prognostic indicators. A number of sensitivity analyses did not alter our conclusions. Interpretation: Depressive symptom severity had a strong association with prognosis independent of treatment. The duration of depressive symptoms, duration of anxiety symptoms, panic disorder and past antidepressant use were all associated with prognosis independent of depressive symptom severity and treatment. Consideration of these prognostic indicators could be clinically important for determining prognosis and inform patients and clinicians about likely outcomes in the clinical management of depression. Funding Statement: This work was supported by the Wellcome Trust through a Clinical Research Fellowship to JB (201292/Z/16/Z), Medical Research Council (Programme for IW: MC_UU_12023/21), MQ Foundation (for ZC: MQDS16/72), the Higher Education Funding Council for England, the National Institute of Health Research (NIHR), NIHR University College London Hospitals Biomedical Research Centre (RS, KC, PB, and SP), University College London (GA, GL), University of Pennsylvania (RDR), Vanderbilt University (SDH), University of Southampton (TK), University of Exeter (EW), and University of York (SG). Declaration of Interests: All authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: PROSPERO registration: CRD42019129512.

BackgroundAlthough cognitive-behavioural therapy (CBT) is an effective treatment for depression, less than half of patients achieve satisfactory symptom reduction during treatment. Targeting known psychopathological processes such as rumination may increase treatment efficacy. The aim of this study was to test whether adding group rumination-focused CBT (RFCBT) that explicitly targets rumination to routine medical management is superior to adding group CBT to routine medical management in treating major depression.MethodsA total of 131 outpatients with major depression were randomly allocated to 12 sessions group RFCBT v. group CBT, each in addition to routine medical management. The primary outcome was observer-rated symptoms of depression at the end of treatment measured on the Hamilton Rating Scale for Depression. Secondary outcomes were rumination at post-treatment and depressive symptoms at 6 months follow-up (Trial registered: NCT02278224).ResultsRFCBT significantly improved observer-rated depressive symptoms (Cohen's d 0.38; 95% CI 0.03–0.73) relative to group CBT at post-treatment on the primary outcome. No post-treatment differences were found in rumination or in depressive symptoms at 6 months follow-up, although these secondary analyses may have been underpowered.ConclusionsThis is the first randomized controlled trial providing evidence of benefits of RFCBT in major depression compared with CBT. Group RFCBT may be a beneficial alternative to group CBT for major depression.