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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.

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.

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.

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.

BackgroundDespite a growing number of prescriptions for antidepressants (over 70 million in 2018), there is uncertainty about when people with depression might benefit from antidepressant medication and concern that antidepressants are prescribed unnecessarily.ObjectivesThe main objective of the PANDA (What are the indications for Prescribing ANtiDepressAnts that will lead to a clinical benefit?) research programme was to provide more guidance about when antidepressants are likely to benefit people with depression. We aimed to estimate the minimal clinically important difference for commonly used self-administered scales for depression and anxiety, and to understand more about how patients respond to such assessments. We carried out an observational study of patients with depressive symptoms and a placebo-controlled randomised controlled trial of sertraline versus placebo to estimate the treatment effect in UK primary care. The hypothesis was that the severity and duration of symptoms were related to treatment response.DesignThe programme consisted of three phases. The first phase relied on the secondary analysis of existing data extracted from published trials. The second phase was the PANDA cohort study of patients with depressive symptoms who presented to primary care and were followed up 2, 4 and 6 weeks after a baseline assessment. Both quantitative and qualitative methods were used in the analysis. The third phase was a multicentre randomised placebo-controlled double-blind trial of sertraline versus placebo in patients presenting to primary care with depressive symptoms.SettingUK primary care in Bristol, London, Liverpool and York.ParticipantsPatients aged 18–74 years who were experiencing depressive symptoms in primary care. Eligibility for the PANDA randomised controlled trial included that there was uncertainty about the benefits about treatment with an antidepressant.InterventionsIn the PANDA randomised controlled trial, patients were individually randomised to 100 mg daily of sertraline or an identical placebo. The PANDA cohort study was an observational study.Main outcome measuresDepressive symptoms measured using the Patient Health Questionnaire were the primary outcome for the randomised controlled trial. Other outcomes included anxiety symptoms using the Generalised Anxiety Disorder-7; depressive symptoms using the Beck Depression Inventory, version 2; health-related quality of life; self-reported improvement; and cost-effectiveness.ResultsThe secondary analysis of existing randomised controlled trials [GENetic and clinical Predictors Of treatment response in Depression (GenPod), TREAting Depression with physical activity (TREAD) and Clinical effectiveness and cost-effectiveness of cognitive Behavioural Therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care (CoBalT)] found evidence that the minimal clinically important difference increased as the initial severity of depressive symptoms rose. Our estimates of minimal clinically important difference were a 17% and 18% reduction in Beck Depression Inventory scores for GenPod and TREAD, respectively. In CoBalT, a 32% reduction corresponded to the minimal clinically important difference but the participants in this study had depression that had not responded to antidepressants. In the PANDA study cohort, and from our analyses in existing data, we found that the minimal clinically important difference varies considerably with the initial severity of depressive and anxiety symptoms. Expressing the minimal clinically important difference as a percentage reduction reduces this variation at higher scores, but at low scores the percentage reduction increased substantially. The results from the qualitative studies pointed out many limitations of the Patient Health Questionnaire-9 items in assessing change and recovery from depression. In the PANDA randomised controlled trial, there was no evidence that sertraline resulted in a reduction in depressive symptoms within 6 weeks of randomisation, but there was some evidence of a reduction by 12 weeks. However, sertraline led to a reduction in anxiety symptoms, an improvement of mental health-related quality of life and an increased likelihood of reporting improvement. The mean Patient Health Questionnaire-9 items score at 6 weeks was 7.98 (standard deviation 5.63) in the sertraline group and 8.76 (standard deviation 5.86) in the placebo group (5% relative reduction, 95% confidence interval –7% to 15%;p = 0.41). Of the secondary outcomes, there was strong evidence that sertraline reduced anxiety symptoms (Generalised Anxiety Disorder-7 score reduced by 17% (95% confidence interval 9% to 25%;p = 0.00005). Sertraline had a high probability (> 90%) of being cost-effective at 12 weeks. The PANDA randomised controlled trial found no evidence that treatment response or cost-effectiveness was related to severity or duration of depressive symptoms. The minimal clinically important difference estimates suggested that sertraline’s effect on anxiety, but not on depression, was likely to be clinically important.LimitationsThe results from the randomised controlled trial and the estimates of minimal clinically important difference were not sufficiently precise to provide specific clinical guidance for individuals. We had low power in testing whether or not initial severity and duration of depressive symptoms are related to treatment response.ConclusionsThe results of the trial support the use of sertraline and probably other selective serotonin reuptake inhibitors because of their action in reducing anxiety symptoms and the likelihood of longer-term benefit on depressive symptoms. Sertraline could be prescribed for anxiety symptoms that commonly occur with depression and many patients will experience a clinical benefit. The Patient Health Questionnaire-9 items and similar self-administered scales should not be used on their own to assess clinical outcome, but should be supplemented with further clinical assessment.Future workWe need to examine the longer-term effects of antidepressant treatment. We need more precise estimates of the treatment effects and minimal clinically important difference at different severities to provide more specific guidance for individuals. However, the methods we have developed provide an approach towards providing such detailed guidance.Trial registrationCurrent Controlled Trials ISRCTN84544741 and EudraCT number 2013-003440-22.FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 7, No. 10. See the NIHR Journals Library website for further project information.

BACKGROUND: Depression is a common mental health condition with considerable negative impact on health and well-being. Although antidepressants are recommended as first-line treatment, there is limited evidence regarding the cost effectiveness of long-term maintenance antidepressants for preventing relapse.OBJECTIVES: Our objective was to calculate the mean incremental costs and quality-adjusted life-years (QALYs) over 12 months of discontinuing long-term antidepressant medication in well patients compared with maintenance, using patient-level trial data.METHODS: We conducted a cost-utility analysis of 478 participants from 150 UK general practices recruited to a randomised, double-blind trial (ANTLER). QALYs were calculated from EQ-5D-5L and 12-Item Short Form survey (SF-12) results, with primary analysis using the EQ-5D-5L value set for England. Resource use was collected from primary care patient electronic medical records and self-completed questionnaires capturing mental-health-related resource use. Costs were calculated by applying standard UK unit costs to resource use. Adjustments were made for baseline variables.RESULTS: Participants randomised to discontinuation had significantly worse utility scores at 3 months (- 0.032; 95% confidence interval [CI] - 0.053 to - 0.011) but no significant difference in QALYs (- 0.011; 95% CI - 0.026 to 0.003) or costs (£3.11; 95% CI - 41.28 to 47.50) at 12 months. The probability that discontinuation was cost effective compared with maintenance was 12.9% at a threshold of £20,000 per QALY gained.CONCLUSIONS: Discontinuation of antidepressants was unlikely to be cost effective compared with maintenance for currently well patients on long-term antidepressants. However, this analysis provides no information on the wider impact of antidepressants. Our findings provide information on the potential impact of discontinuing long-term maintenance antidepressants and facilitate improving guidance for shared patient-clinician decision making.TRIAL REGISTRATION: EudraCT number 2015-004210-26; ISRCTN number ISRCTN15969819.

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 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.

BACKGROUNDPatients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting.METHODSWe conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings.RESULTSA total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; PCONCLUSIONSAmong patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819. opens in new tab.)

OBJECTIVE: To investigate whether continuity of care in family practice reduces unplanned hospital use for people with serious mental illness (SMI).DATA SOURCES: Linked administrative data on family practice and hospital utilization by people with SMI in England, 2007-2014.STUDY DESIGN: This observational cohort study used discrete-time survival analysis to investigate the relationship between continuity of care in family practice and unplanned hospital use: emergency department (ED) presentations, and unplanned admissions for SMI and ambulatory care-sensitive conditions (ACSC). The analysis distinguishes between relational continuity and management/ informational continuity (as captured by care plans) and accounts for unobserved confounding by examining deviation from long-term averages.DATA COLLECTION/EXTRACTION METHODS: Individual-level family practice administrative data linked to hospital administrative data.PRINCIPAL FINDINGS: Higher relational continuity was associated with 8-11 percent lower risk of ED presentation and 23-27 percent lower risk of ACSC admissions. Care plans were associated with 29 percent lower risk of ED presentation, 39 percent lower risk of SMI admissions, and 32 percent lower risk of ACSC admissions.CONCLUSIONS: Family practice continuity of care can reduce unplanned hospital use for physical and mental health of people with SMI.

Objective:Although U.K. and international guidelines recommend monotherapy, antipsychotic polypharmacy among patients with serious mental illness is common in clinical practice. However, empirical evidence on its effectiveness is scarce. Therefore, the authors estimated the effectiveness of antipsychotic polypharmacy relative to monotherapy in terms of health care utilization and mortality.Methods:Primary care data from Clinical Practice Research Datalink, hospital data from Hospital Episode Statistics, and mortality data from the Office of National Statistics were linked to compile a cohort of patients with serious mental illness in England from 2000 to 2014. The antipsychotic prescribing profile of 17,255 adults who had at least one antipsychotic drug record during the period of observation was constructed from primary care medication records. Survival analysis models were estimated to identify the effect of antipsychotic polypharmacy on the time to first occurrence of each of three outcomes: unplanned hospital admissions (all cause), emergency department (ED) visits, and mortality.Results:Relative to monotherapy, antipsychotic polypharmacy was not associated with increased risk of unplanned hospital admission (hazard ratio [HR]=1.14; 95% confidence interval [CI]=0.98–1.32), ED visit (HR=0.95; 95% CI=0.80–1.14), or death (HR=1.02; 95% CI=0.76–1.37). Relative to not receiving antipsychotic medication, monotherapy was associated with a reduced hazard of unplanned admissions to the hospital and ED visits, but it had no effect on mortality.Conclusions:The study results support current guidelines for antipsychotic monotherapy in routine clinical practice. However, they also suggest that when clinicians have deemed antipsychotic polypharmacy necessary, health care utilization and mortality are not affected.

PURPOSE:We aimed to determine the effectiveness of interventions to manage antidepressant discontinuation, and the outcomes for patients.METHODS:We conducted a systematic review with narrative synthesis and meta-analysis of studies published to March 2017. Studies were eligible for inclusion if they were randomized controlled trials, quasi-experimental studies, or observational studies assessing interventions to facilitate discontinuation of antidepressants for depression in adults. Our primary outcomes were antidepressant discontinuation and discontinuation symptoms. Secondary outcomes were relapse/recurrence; quality of life; antidepressant reduction; and sexual, social, and occupational function.RESULTS:Of 15 included studies, 12 studies (8 randomized controlled trials, 2 single-arm trials, 2 retrospective cohort studies) were included in the synthesis. None were rated as having high risk for selection or detection bias. Two studies prompting primary care clinician discontinuation with antidepressant tapering guidance found 6% and 7% of patients discontinued, vs 8% for usual care. Six studies of psychological or psychiatric treatment plus tapering reported cessation rates of 40% to 95%. Two studies reported a higher risk of discontinuation symptoms with abrupt termination. At 2 years, risk of relapse/recurrence was lower with cognitive behavioral therapy plus taper vs clinical management plus taper (15% to 25% vs 35% to 80%: risk ratio = 0.34; 95% CI, 0.18-0.67; 2 studies). Relapse/recurrence rates were similar for mindfulness-based cognitive therapy with tapering and maintenance antidepressants (44% to 48% vs 47% to 60%; 2 studies).CONCLUSIONS:Cognitive behavioral therapy or mindfulness-based cognitive therapy can help patients discontinue antidepressants without increasing the risk of relapse/recurrence, but are resource intensive. More scalable interventions incorporating psychological support are needed.

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 Depression and anxiety are the most frequent indication for which antidepressants are prescribed. Long-term antidepressant use is driving much of the internationally observed rise in antidepressant consumption. Surveys of antidepressant users suggest that 30% to 50% of long-term antidepressant prescriptions had no evidence-based indication. Unnecessary use of antidepressants puts people at risk of adverse events. However, high-certainty evidence is lacking regarding the effectiveness and safety of approaches to discontinuing long-term antidepressants. Objectives To assess the effectiveness and safety of approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults. Search methods We searched all databases for randomised controlled trials (RCTs) until January 2020. Selection criteria We included RCTs comparing approaches to discontinuation with continuation of antidepressants (or usual care) for people with depression or anxiety who are prescribed antidepressants for at least six months. Interventions included discontinuation alone (abrupt or taper), discontinuation with psychological therapy support, and discontinuation with minimal intervention. Primary outcomes were successful discontinuation rate, relapse (as defined by authors of the original study), withdrawal symptoms, and adverse events. Secondary outcomes were depressive symptoms, anxiety symptoms, quality of life, social and occupational functioning, and severity of illness. Data collection and analysis We used standard methodological procedures as expected by Cochrane. Main results We included 33 studies involving 4995 participants. Nearly all studies were conducted in a specialist mental healthcare service and included participants with recurrent depression (i.e. two or more episodes of depression prior to discontinuation). All included trials were at high risk of bias. The main limitation of the review is bias due to confounding withdrawal symptoms with symptoms of relapse of depression. Withdrawal symptoms (such as low mood, dizziness) may have an effect on almost every outcome including adverse events, quality of life, social functioning, and severity of illness. Abrupt discontinuation Thirteen studies reported abrupt discontinuation of antidepressant. Very low-certainty evidence suggests that abrupt discontinuation without psychological support may increase risk of relapse(hazard ratio (HR) 2.09, 95% confidence interval (CI) 1.59 to 2.74; 1373 participants, 10 studies) and there is insufficient evidence of its effect on adverse events (odds ratio (OR) 1.11, 95% CI 0.62 to 1.99; 1012 participants, 7 studies; I-2 = 37%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of abrupt discontinuation on withdrawal symptoms (1 study) is very uncertain. None of these studies included successful discontinuation rate as a primary endpoint. Discontinuation by "taper" Eighteen studies examined discontinuation by "tapering" (one week or longer). Most tapering regimens lasted four weeks or less. Very low-certainty evidence suggests that "tapered" discontinuation may lead to higher risk of relapse (HR 2.97, 95% CI 2.24 to 3.93; 1546 participants, 13 studies) with no or little difference in adverse events (OR 1.06, 95% CI 0.82 to 1.38; 1479 participants, 7 studies; I-2 = 0%) compared to continuation of antidepressants, without specific assessment of withdrawal symptoms. Evidence about the effects of discontinuation on withdrawal symptoms (1 study) is very uncertain. Discontinuation with psychological support Four studies reported discontinuation with psychological support. Very low-certainty evidence suggests that initiation of preventive cognitive therapy (PCT), or MBCT, combined with "tapering" may result in successful discontinuation rates of 40% to 75% in the discontinuation group (690 participants, 3 studies). Data from control groups in these studies were requested but are not yet available. Low-certainty evidence suggests that discontinuation combined with psychological intervention may result in no or little effect on relapse (HR 0.89, 95% CI 0.66 to 1.19; 690 participants, 3 studies) compared to continuation of antidepressants. Withdrawal symptoms were not measured. Pooling data on adverse events was not possible due to insufficient information (3 studies). Discontinuation with minimal intervention Low-certainty evidence from one study suggests that a letter to the general practitioner (GP) to review antidepressant treatment may result in no or little effect on successful discontinuation rate compared to usual care (6% versus 8%; 146 participants, 1 study) or on relapse (relapse rate 26% vs 13%; 146 participants, 1 study). No data on withdrawal symptoms nor adverse events were provided. None of the studies used low-intensity psychological interventions such as online support or a changed pharmaceutical formulation that allows tapering with low doses over several months. Insufficient data were available for the majority of people taking antidepressants in the community (i.e. those with only one or no prior episode of depression), for people aged 65 years and older, and for people taking antidepressants for anxiety. Authors' conclusions Currently, relatively few studies have focused on approaches to discontinuation of long-term antidepressants. We cannot make any firm conclusions about effects and safety of the approaches studied to date. The true effect and safety are likely to be substantially different from the data presented due to assessment of relapse of depression that is confounded by withdrawal symptoms. All other outcomes are confounded with withdrawal symptoms. Most tapering regimens were limited to four weeks or less. In the studies with rapid tapering schemes the risk of withdrawal symptoms may be similar to studies using abrupt discontinuation which may influence the effectiveness of the interventions. Nearly all data come from people with recurrent depression. There is an urgent need for trials that adequately address withdrawal confounding bias, and carefully distinguish relapse from withdrawal symptoms. Future studies should report key outcomes such as successful discontinuation rate and should include populations with one or no prior depression episodes in primary care, older people, and people taking antidepressants for anxiety and use tapering schemes longer than 4 weeks.

Background By 2050, worldwide dementia prevalence is expected to triple. Affordable, scalable interventions are required to support protective behaviours such as physical activity, cognitive training and healthy eating. This paper outlines the theory-, evidence- and person-based development of ‘Active Brains’: a multi-domain digital behaviour change intervention to reduce cognitive decline amongst older adults. Methods During the initial planning phase, scoping reviews, consultation with PPI contributors and expert co-investigators and behavioural analysis collated and recorded evidence that was triangulated to inform provisional ‘guiding principles’ and an intervention logic model. The following optimisation phase involved qualitative think aloud and semi-structured interviews with 52 older adults with higher and lower cognitive performance scores. Data were analysed thematically and informed changes and additions to guiding principles, the behavioural analysis and the logic model which, in turn, informed changes to intervention content. Results Scoping reviews and qualitative interviews suggested that the same intervention content may be suitable for individuals with higher and lower cognitive performance. Qualitative findings revealed that maintaining independence and enjoyment motivated engagement in intervention-targeted behaviours, whereas managing ill health was a potential barrier. Social support for engaging in such activities could provide motivation, but was not desirable for all. These findings informed development of intervention content and functionality that appeared highly acceptable amongst a sample of target users. Conclusions A digitally delivered intervention with minimal support appears acceptable and potentially engaging to older adults with higher and lower levels of cognitive performance. As well as informing our own intervention development, insights obtained through this process may be useful for others working with, and developing interventions for, older adults and/or those with cognitive impairment.

BACKGROUND The number of people receiving antidepressants has increased in the past 3 decades, mainly because of people staying on them longer. However, in many cases long-term treatment is not evidence based and risks increasing side effects. Additionally, prompting general practitioners (GPs) to review medication does not improve the rate of appropriate discontinuation. Therefore, GPs and other health professionals may need help to support patients discontinuing antidepressants in primary care. OBJECTIVE This study aims to develop a digital intervention to support practitioners in helping patients discontinue inappropriate long-term antidepressants (as part of a wider intervention package including a patient digital intervention and patient telephone support). METHODS A prototype digital intervention called Advisor for Health Professionals (ADvisor HP) was planned and developed using theory, evidence, and a person-based approach. The following elements informed development: a literature review and qualitative synthesis, an in-depth qualitative study, the development of guiding principles for design elements, and theoretical behavioral analyses. The intervention was then optimized through think-aloud qualitative interviews with health professionals while they were using the prototype intervention. RESULTS Think-aloud qualitative interviews with 19 health professionals suggested that the digital intervention contained useful information and was readily accessible to practitioners. The development work highlighted a need for further guidance on drug tapering schedules for practitioners and clarity about who is responsible for broaching the subject of discontinuation. Practitioners highlighted the need to have information in easily and quickly accessible formats because of time constraints in day-to-day practice. Some GPs felt that some information was already known to them but understood why this was included. Practitioners differed in their ideas about how they would use ADvisor HP in practice, with some preferring to read the resource in its entirety and others wanting to dip in and out as needed. Changes were made to the wording and structure of the intervention in response to the feedback provided. CONCLUSIONS ADvisor HP is a digital intervention that has been developed using theory, evidence, and a person-based approach. The optimization work suggests that practitioners may find this tool to be useful in supporting the reduction of long-term antidepressant use. Further quantitative and qualitative evaluation through a randomized controlled trial is needed to examine the feasibility, effectiveness, and cost-effectiveness of the intervention.

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: Subgrouping methods have the potential to support treatment decision making for patients with depression. Such approaches have not been used to study the continued course of depression or likelihood of relapse following treatment. Method: Data from individual participants of seven randomised controlled trials were analysed. Latent profile analysis was used to identify subgroups based on baseline characteristics. Associations between profiles and odds of both continued chronic depression and relapse up to one year post-treatment were explored. Differences in outcomes were investigated within profiles for those treated with antidepressants, psychological therapy, and usual care. Results: Seven profiles were identified; profiles with higher symptom severity and long durations of both anxiety and depression at baseline were at higher risk of relapse and of chronic depression. Members of profile five (likely long durations of depression and anxiety, moderately-severe symptoms, and past antidepressant use) appeared to have better outcomes with psychological therapies: antidepressants vs. psychological therapies (OR (95% CI) for relapse = 2.92 (1.24–6.87), chronic course = 2.27 (1.27–4.06)) and usual care vs. psychological therapies (relapse = 2.51 (1.16–5.40), chronic course = 1.98 (1.16–3.37)). Conclusions: Profiles at greater risk of poor outcomes could benefit from more intensive treatment and frequent monitoring. Patients in profile five may benefit more from psychological therapies than other treatments. Keywords: depression; primary care; latent profile analysis; personalised medicine; patient stratification

Background Increasing physical activity, improving diet, and performing brain training exercises are associated with reduced cognitive decline in older adults. Objective In this paper, we describe a feasibility trial of the Active Brains intervention, a web-based digital intervention developed to support older adults to make these 3 healthy behavior changes associated with improved cognitive health. The Active Brains trial is a randomized feasibility trial that will test how accessible, acceptable, and feasible the Active Brains intervention is and the effectiveness of the study procedures that we intend to use in the larger, main trial. Methods In the randomized controlled trial (RCT), we use a parallel design. We will be conducting the intervention with 2 populations recruited through GP practices (family practices) in England from 2018 to 2019: older adults with signs of cognitive decline and older adults without any cognitive decline. Trial participants were randomly allocated to 1 of 3 study groups: usual care, the Active Brains intervention, or the Active Brains website plus brief support from a trained coach (over the phone or by email). The main outcomes are performance on cognitive tasks, quality of life (using EuroQol-5D 5 level), Instrumental Activities of Daily Living, and diagnoses of dementia. Secondary outcomes (including depression, enablement, and health care costs) and process measures (including qualitative interviews with participants and supporters) will also be collected. The trial has been approved by the National Health Service Research Ethics Committee (reference 17/SC/0463). Results Results will be published in peer-reviewed journals, presented at conferences, and shared at public engagement events. Data collection was completed in May 2020, and the results will be reported in 2021. Conclusions The findings of this study will help us to identify and make important changes to the website, the support received, or the study procedures before we progress to our main randomized phase III trial. Trial Registration International Standard Randomized Controlled Trial Number 23758980; http://www.isrctn.com/ISRCTN23758980 International Registered Report Identifier (IRRID) DERR1-10.2196/18929

What you need to know Patient reported outcome measures (PROMs) are questionnaires or brief interviews assessing patients’ symptoms, social functioning, and health related quality of life.1 PROMs provide feedback on patients’ responses to treatment, so healthcare practitioners may then adjust treatment or refer for alternative interventions.1 Their use in the assessment of severity of depression and monitoring is widely promoted in primary care, psychological therapy, and mental healthcare settings in the UK, US, and Europe (box 1). In the NHS England Improving Access to Psychological Therapies (IAPT) programme, PROMs for depression, anxiety, and social functioning are routinely administered at every treatment session.2 Box 1 ### Organisations recommending the use of PROMs for monitoring outcomes in the treatment of depressionRETURN TO TEXT PROMs are relatively quick surrogate measures for longer, interview-based assessments of symptoms and functioning. PROMs provide standardised results, readily understandable to other practitioners, and to patients themselves after brief explanations of their meaning. Similar measures can be used to screen for depression and aid …

Antidepressant prescribing has increased year on year since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the 1980s. More than 10% of adults in England are now taking antidepressants for depression/anxiety, with a median length of treatment of more than 2 years, but antidepressants can cause side effects and withdrawal symptoms which increase with longer use. Surveys of antidepressant users suggest 30-50% have no evidence-based indication to continue, but coming off antidepressants is often difficult due to fears of relapse, withdrawal symptoms and a lack of psychological treatments to replace maintenance treatment and prevent relapse. GPs should not prescribe antidepressants routinely for mild depressive/anxiety symptoms. Patients starting antidepressants should be advised that they are to be taken for a limited period only, and that there is a risk of withdrawal problems on stopping them. Prescribers should actively review long-term antidepressant use and suggest coming off them slowly to patients who are well. The relationship between SSRI dose and serotonin transporter receptor occupancy suggests that hyperbolic tapering regimes may be helpful for patients with troubling withdrawal symptoms who cannot stop treatment within 4-8 weeks, and tapering strips can allow carefully titrated slower dose reduction over some months. Internet and telephone support to patients wanting to reduce their antidepressants is being trialled in the REDUCE programme. More research is needed to establish the incidence of withdrawal symptoms in representative samples of patients coming off antidepressants, and large randomised controlled trials are needed to test different tapering strategies.

Background Benefits to patients from reduced depression have been shown from monitoring progress with patient-reported outcome measures (PROMs) in psychological therapy and mental health settings. This approach has not yet been researched in the United Kingdom for primary care, which is where most people with depression are treated in the United Kingdom. Methods This is a parallel-group cluster randomised trial with 1:1 allocation to intervention and control. Patients who are age 18+ years, with a new episode of depressive disorder/symptoms, meet the inclusion criteria. Patients with current depression treatment, comorbid dementia/psychosis/substance misuse/suicidal ideas are excluded. The intervention includes the Administration of Patient Health Questionnaire (PHQ-9) as a PROM within 2 weeks of diagnosis and at follow-up 4 weeks later. General practitioners are trained in interpreting scores and asked to take them into account in their treatment decisions. Patients are given written feedback on scores and suggested treatments. The primary outcome measure is Depression on the Beck Depression Inventory BDI-II at 12 weeks. Secondary outcomes include BDI-II at 26 weeks, changes in drug treatments and referrals, social functioning (Work & Social Adjustment Scale) and quality of life (EQ-5D) at 12 and 26 weeks, service use over 26 weeks (modified Client Services Receipt Inventory) to calculate NHS costs, and patient satisfaction at 26 weeks (Medical Informant Satisfaction Scale). The sample includes 676 total participants from 113 practices across three centres. Randomisation is achieved by computerised sequence generation. Blinding is impossible given the nature of the intervention (self-report outcome measures prevent rating bias). Differences at 12 and 26 weeks between intervention and controls in depression, social functioning and quality of life are analysed using linear mixed models, adjusted for socio-demographics, baseline depression, anxiety, and clustering, while including practice as a random effect. Patient satisfaction, quality of life (QALYs) and costs over 26 weeks will be compared between arms. Qualitative process analysis includes interviews with 15–20 GP/NPs and 15–20 patients per arm to reflect trial results and implementation issues, using Normalization Process Theory as a theoretical framework. Discussion If PROMs are helpful in improving patient outcomes for depression even to a small extent, then they are likely to be good value for money, given their low cost. The benefits could be considerable, given that depression is common, disabling, and costly. Trial registration ISRCTN no: 17299295. Registered 1st October 2018.

Background By 2050 worldwide dementia prevalence is expected to triple, rising to 152 million. Affordable, scalable interventions are required to support protective behaviours such as physical activity, cognitive training and healthy eating. This paper outlines the development of ‘Active Brains’: a multi-domain digital behaviour change intervention to reduce cognitive decline amongst older adults, and key findings arising from this process. Methods A theory-, evidence- and person-based approach to intervention development was undertaken. Scoping reviews and behavioural analysis contributed to intervention planning. Optimisation involved qualitative interviews with 52 older adults with higher and lower cognitive performance scores. Data were analysed thematically and informed changes. Results The development process synthesised findings from planning and optimisation activities. Scoping reviews and qualitative interviews suggested that the same intervention content should be suitable for individuals with higher and lower cognitive performance. Qualitative findings revealed that maintaining independence and enjoyment motivated engagement in intervention-targeted behaviours, whereas managing ill health was a potential barrier. Social support for engaging in such activities could provide motivation, but was not desirable for all. These findings informed development of highly acceptable intervention content and functionality for target users. Conclusions A digitally-delivered intervention with minimal support appears acceptable and potentially engaging to older adults with higher and lower levels of cognitive performance. As well as informing our own intervention, the insights obtained through our development process may be useful for others working with, and developing interventions for, older adults and/or those with cognitive impairment.

BACKGROUND Increasing physical activity, improving diet, and performing brain training exercises are associated with reduced cognitive decline in older adults. OBJECTIVE In this paper, we describe a feasibility trial of the Active Brains intervention, a web-based digital intervention developed to support older adults to make these 3 healthy behavior changes associated with improved cognitive health. The Active Brains trial is a randomized feasibility trial that will test how accessible, acceptable, and feasible the Active Brains intervention is and the effectiveness of the study procedures that we intend to use in the larger, main trial. METHODS In the randomized controlled trial (RCT), we use a parallel design. We will be conducting the intervention with 2 populations recruited through GP practices (family practices) in England from 2018 to 2019: older adults with signs of cognitive decline and older adults without any cognitive decline. Trial participants were randomly allocated to 1 of 3 study groups: usual care, the Active Brains intervention, or the Active Brains website plus brief support from a trained coach (over the phone or by email). The main outcomes are performance on cognitive tasks, quality of life (using EuroQol-5D 5 level), Instrumental Activities of Daily Living, and diagnoses of dementia. Secondary outcomes (including depression, enablement, and health care costs) and process measures (including qualitative interviews with participants and supporters) will also be collected. The trial has been approved by the National Health Service Research Ethics Committee (reference 17/SC/0463). RESULTS Results will be published in peer-reviewed journals, presented at conferences, and shared at public engagement events. Data collection was completed in May 2020, and the results will be reported in 2021. CONCLUSIONS The findings of this study will help us to identify and make important changes to the website, the support received, or the study procedures before we progress to our main randomized phase III trial. CLINICALTRIAL International Standard Randomized Controlled Trial Number 23758980; http://www.isrctn.com/ISRCTN23758980 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/18929

BackgroundBy 2050 worldwide dementia prevalence is expected to triple, rising to 152 million. Affordable, scalable interventions are required to support protective behaviours such as physical activity, cognitive training and healthy eating. This paper outlines the development of ‘Active Brains’: a multi-domain digital behaviour change intervention to reduce cognitive decline amongst older adults, and key findings arising from this process.MethodsA theory-, evidence- and person-based approach to intervention development was undertaken. Scoping reviews and behavioural analysis contributed to intervention planning. Optimisation involved qualitative interviews with 52 older adults with higher and lower cognitive performance scores. Data were analysed thematically and informed changes.ResultsThe development process synthesised findings from planning and optimisation activities. Scoping reviews and qualitative interviews suggested that the same intervention content should be suitable for individuals with higher and lower cognitive performance. Qualitative findings revealed that maintaining independence and enjoyment motivated engagement in intervention-targeted behaviours, whereas managing ill health was a potential barrier. Social support for engaging in such activities could provide motivation, but was not desirable for all. These findings informed development of highly acceptable intervention content and functionality for target users.ConclusionsA digitally-delivered intervention with minimal support appears acceptable and potentially engaging to older adults with higher and lower levels of cognitive performance. As well as informing our own intervention, the insights obtained through our development process may be useful for others working with, and developing interventions for, older adults and/or those with cognitive impairment.

The fundamental building blocks of modern mental health services (primary care provision, inpatient wards, and some form of multi-disciplinary community team) are broadly established in high-income countries. In low- and middle-income countries, the availability of each of these three components is highly variable and investment often reflects local traditions and practices. Planning rarely begins with a blank sheet, and while it should be informed by local needs assessment and epidemiology, it is likely to be an exercise in the possible. Strengthening primary care provision and establishing multi-disciplinary teams that can provide outreach to the most severely ill are key to success. Organizational simplicity and stability, coupled with effective liaison with social care, mark effective systems.

ObjectivesWe aimed to develop a digital intervention to support antidepressant discontinuation in UK primary care that is scalable, accessible, safe and feasible. In this paper, we describe the development using a theory, evidence and person-based approach.DesignIntervention development using a theory, evidence and person-based approach.SettingPrimary Care in the South of England.ParticipantsFifteen participants with a range of antidepressant experience took part in ‘think aloud’ interviews for intervention optimisation.InterventionOur digital intervention prototype (called ‘ADvisor’) was developed on the basis of a planning phase consisting of qualitative and quantitative reviews, an in-depth qualitative study, the development of guiding principles and a theory-based behavioural analysis. Our optimisation phase consisted of ‘think aloud’ interviews where the intervention was iteratively refined.ResultsThe qualitative systematic review and in-depth qualitative study highlighted the centrality of fear of depression relapse as a key barrier to discontinuation. The quantitative systematic review showed that psychologically informed approaches such as cognitive–behavioural therapy were associated with greater rates of discontinuation than simple advice to reduce. Following a behavioural diagnosis based on the behaviour change wheel, social cognitive theory provided a theoretical basis for the intervention. The intervention was optimised on the basis of think aloud interviews, where participants suggested they like the flexibility of the system and found it reassuring. Changes were made to the tone of the material and the structure was adjusted based on this qualitative feedback.Conclusions‘ADvisor’ is a theory, evidence and person-based digital intervention designed to support antidepressant discontinuation. The intervention was perceived as helpful and reassuring in optimisation interviews. Trials are now needed to determine the feasibility, clinical and cost-effectiveness of this approach.

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.