Maintenance or Discontinuation of Antidepressants in Primary Care.

BACKGROUND: Patients 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. METHODS: We 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. RESULTS: A 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; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among 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.).

Clinical factors associated with relapse in depression in a sample of UK primary care patients who have been on long-term antidepressant treatment.

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

The lived experience of withdrawal from Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants: A qualitative interview study.

BACKGROUND: Our knowledge of the broader impacts of antidepressant withdrawal, beyond physical side effects, is limited. Further research is needed to investigate the lived experiences of withdrawal, to aid clinicians on how to guide patients through the process. AIM: To explore antidepressant users' experiences and views on the withdrawal process and how it affected their quality of life across multiple life domains. DESIGN AND SETTING: We conducted in-depth qualitative interviews with 20 individuals from the community who had attempted to withdraw from Serotonin Reuptake Inhibitor antidepressants in the past year. METHOD: Semi-structured interviews were conducted online. A topic guide was used to ensure consistency across interviews. The interviews were audio-recorded and transcribed verbatim and analysed using inductive reflexive thematic analysis. RESULTS: Five themes were generated. The first highlighted the challenges of managing the release from emotional blunting and cognitive suppression following antidepressant discontinuation. The second related to the negative impact of withdrawal on close relationships and social interactions. The third showed that concurrent with negative physical symptoms, there was a positive impact on health (exercise was reported by some as a coping mechanism). The fourth theme focused on support from GPs and families, emphasising the importance of mental health literacy in others. The final theme underscored the importance of gradual and flexible tapering in enabling a manageable withdrawal experience, and the consideration of timing. CONCLUSION: The lived experience of withdrawal significantly impacts individuals' well-being. Participants emphasised that withdrawal is not just about physical side effects but also affects their emotional, cognitive, and social functioning. PATIENT AND PUBLIC INVOLVEMENT (PPI): Eight people attended individual online meetings to share their experiences of antidepressant withdrawal to help inform the study design and recruitment strategy. Insights from these meetings informed the development of the topic guide. Questions about GP involvement, family relationships, and mood and thinking changes were included based on this PPI work. This ensured the inclusion of topics important to antidepressant users and facilitated the researcher's questioning during the interviews.

Patients' and Therapists' Views of Integrated Online CBT for Depression.

BACKGROUND: CBT is an effective treatment for depression, but access varies across the United Kingdom. Online CBT increases access. The INTERACT platform was designed to support patient engagement in CBT, enabling therapists to deliver high-intensity CBT via typed instant messaging and allowing patients and therapists access to an integrated online library of resources during and between sessions. METHODS: The INTERACT trial aimed to evaluate this integrated approach to delivering CBT for primary care patients with depression. A nested qualitative study was conducted within the trial. Interviews were conducted with 20 patients who received the intervention, 9 therapists who delivered it and 3 therapist supervisors. Data were analysed using thematic analysis. RESULTS: The combination of receiving support from a therapist and having access to integrated online CBT resources enabled patients to better manage their depression. Platform benefits included the opportunity to review transcripts to clarify how to complete homework tasks and track progress in managing their depression. The typing process allowed reflection and a focused discussion. However, less could be covered than during an in-person session, which reduced therapists' expectations around goal setting. Patients who did not complete therapy struggled with the typing and found the CBT approach too demanding. CONCLUSION: Findings highlight the importance of establishing patient and therapist goals and expectations about what can be achieved in CBT mediated by typing. Some patients are comfortable communicating via typing and are motivated to utilise online resources in between sessions. Exploring the benefits and challenges of typed CBT with patients will enable them to make an informed choice about referral for this novel approach to therapy. PATIENT OR PUBLIC CONTRIBUTION: Patients, service users and members of the public were involved in the study design and management. Substantial pilot work gathered stakeholder feedback and informed the design of the intervention, before undertaking the RCT. Coauthor P.L. is a service user representative co-applicant and member of the management group responsible for developing the intervention and the trial. Two PPI members sit on the Independent Steering Committee. PPI members provided valuable feedback on the study resources and documents.

Neuropsychological markers of antidepressant action: a secondary analysis of the ANTLER randomised controlled trial.

BACKGROUND: Antidepressants have been proposed to act via their influence on emotional processing. We investigated the effect of discontinuing maintenance antidepressant treatment on positive and negative self-referential recall and the association between self-referential recall and risk of relapse. METHODS: The ANTLER trial was a large (N = 478) pragmatic double-blind trial investigating the clinical effectiveness of long-term antidepressant treatment for preventing relapse in primary care patients. Participants were randomised to continue their maintenance antidepressants or discontinue via a taper to placebo. We analysed memory for positive and negative personality descriptors, assessed at baseline, 12- and 52-week follow-up. RESULTS: The recall task was completed by 437 participants. There was no evidence of an effect of discontinuation on self-referential recall at 12 [positive recall ratio 1.00, 95% CI (0.90-1.11), p = 0.93; negative recall ratio 1.00 (0.87-1.14), p = 0.87] or 52 weeks [positive recall ratio 1.03 (0.91-1.17), p = 0.62; negative recall ratio 1.00 (0.86-1.15), p = 0.96; ratios larger than one indicate higher recall in the discontinuation group], and no evidence of an association between recall at baseline or 12 weeks and later relapse [baseline, positive hazard ratio (HR) 1.02 (0.93-1.12), p = 0.74; negative HR 1.01 (0.90-1.13), p = 0.87; 12 weeks, positive HR 0.99 (0.89-1.09), p = 0.81; negative HR 0.98 (0.84-1.14), p = 0.78; ratios larger than one indicate a higher frequency of relapse in those with higher recall]. CONCLUSIONS: We found no evidence that discontinuing long-term antidepressants altered self-referential recall or that self-referential recall was associated with risk of relapse. These findings suggest that self-referential recall is not a neuropsychological marker of antidepressant action.

PTSD as a mediator of the relationship between trauma and psychotic experiences.

BACKGROUND: Traumatic experiences are associated with a higher risk of psychotic illnesses, but little is known about potentially modifiable mechanisms underlying this relationship. This study aims to examine whether post-traumatic stress disorder (PTSD) symptoms mediate the relationship between trauma and psychotic experiences (PEs). METHODS: We used data from the Avon Longitudinal Study of Parents and Children to examine whether: PTSD symptoms mediate the relationships between (a) childhood trauma and adolescent PEs (study of adolescent PEs; n = 2952), and (b) childhood/adolescent trauma and PEs in early adulthood (study of adult PEs; n = 2492). We examined associations between variables using logistic regression, and mediation using the parametric g-computation formula. RESULTS: Exposure to trauma was associated with increased odds of PEs (adolescent PEs: ORadjusted 1.48, 95% CI 1.23-1.78; adult PEs: ORadjusted 1.57, 95% CI 1.25-1.98) and PTSD symptoms (adolescent PTSD: ORadjusted 1.59, 95% CI 1.31-1.93; adult PTSD: ORadjusted 1.50, 95% CI 1.36-1.65). The association between PTSD symptoms and PE was stronger in adolescence (ORadjusted 4.63, 95% CI 2.34-9.17) than in adulthood (ORadjusted 1.62, 95% CI 0.80-3.25). There was some evidence that PTSD symptoms mediated the relationship between childhood trauma and adolescent PEs (proportion mediated 14%), though evidence of mediation was weaker for adult PEs (proportion mediated 8%). CONCLUSIONS: These findings are consistent with the hypothesis that PTSD symptoms partly mediate the association between trauma exposure and PEs. Targeting PTSD symptoms might help prevent the onset of psychotic outcomes.

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

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

Sensitivity to missing not at random dropout in clinical trials: Use and interpretation of the trimmed means estimator.

Outcome values in randomized controlled trials (RCTs) may be missing not at random (MNAR), if patients with extreme outcome values are more likely to drop out (eg, due to perceived ineffectiveness of treatment, or adverse effects). In such scenarios, estimates from complete case analysis (CCA) and multiple imputation (MI) will be biased. We investigate the use of the trimmed means (TM) estimator for the case of univariable missingness in one continuous outcome. The TM estimator operates by setting missing values to the most extreme value, and then "trimming" away equal fractions of both groups, estimating the treatment effect using the remaining data. The TM estimator relies on two assumptions, which we term the "strong MNAR" and "location shift" assumptions. We derive formulae for the TM estimator bias resulting from the violation of these assumptions for normally distributed outcomes. We propose an adjusted TM estimator, which relaxes the location shift assumption and detail how our bias formulae can be used to establish the direction of bias of CCA and TM estimates, to inform sensitivity analyses. The TM approach is illustrated in a sensitivity analysis of the CoBalT RCT of cognitive behavioral therapy (CBT) in 469 individuals with 46 months follow-up. Results were consistent with a beneficial CBT treatment effect, with MI estimates closer to the null and TM estimates further from the null than the CCA estimate. We propose using the TM estimator as a sensitivity analysis for data where extreme outcome value dropout is plausible.

Trends in the recording of anxiety in UK primary care: a multi-method approach.

PURPOSE: Anxiety disorders are common. Between 1998 and 2008, in the UK, GP recording of anxiety symptoms increased, but the recording of anxiety disorders decreased. We do not know whether such trends have continued. This study examined recent trends in the recording of anxiety and explored factors that may influence GPs' coding of anxiety. METHODS: We used data from adults (n = 2,569,153) registered with UK general practices (n = 176) that contributed to the Clinical Practice Research Datalink between 2003 and 2018. Incidence rates and 95% confidence intervals were calculated for recorded anxiety symptoms and diagnoses and were stratified by age and gender. Joinpoint regression was used to estimate the years trends changed. In addition, in-depth interviews were conducted with 15 GPs to explore their views and management of anxiety. Interviews were audio-recorded, transcribed verbatim and analysed thematically. RESULTS: The incidence of anxiety symptoms rose from 6.2/1000 person-years at risk (PYAR) in 2003 to 14.7/1000 PYAR in 2018. Between 2003 and 2008, the incidence of anxiety diagnoses fell from 13.2 to 10.1/1000 PYAR; markedly increasing between 2013 and 2018 to 15.3/1000 PYAR. GPs mentioned that they preferred using symptom codes to diagnostic codes to avoid assigning potentially stigmatising or unhelpful labels, and commented on a rise in anxiety in recent years, especially in young adults. CONCLUSION: Recent increases in the recording of both anxiety diagnoses and symptoms may reflect increased presentation to primary care, especially in young adults. There is a clear need to understand the reasons for this, and this knowledge may be critical in the prevention and treatment of anxiety.

Detecting Heterogeneity of Intervention Effects Using Analysis and Meta-analysis of Differences in Variance Between Trial Arms.

BACKGROUND: Randomized controlled trials (RCTs) with continuous outcomes usually only examine mean differences in response between trial arms. If the intervention has heterogeneous effects, then outcome variances will also differ between arms. Power of an individual trial to assess heterogeneity is lower than the power to detect the same size of main effect. METHODS: We describe several methods for assessing differences in variance in trial arms and apply them to a single trial with individual patient data and to meta-analyses using summary data. Where individual data are available, we use regression-based methods to examine the effects of covariates on variation. We present an additional method to meta-analyze differences in variances with summary data. RESULTS: In the single trial, there was agreement between methods, and the difference in variance was largely due to differences in prevalence of depression at baseline. In two meta-analyses, most individual trials did not show strong evidence of a difference in variance between arms, with wide confidence intervals. However, both meta-analyses showed evidence of greater variance in the control arm, and in one example, this was perhaps because mean outcome in the control arm was higher. CONCLUSIONS: Using meta-analysis, we overcame low power of individual trials to examine differences in variance using meta-analysis. Evidence of differences in variance should be followed up to identify potential effect modifiers and explore other possible causes such as varying compliance.

The contribution of depressive 'disorder characteristics' to determinations of prognosis for adults with depression: an individual patient data meta-analysis.

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

Is social support pre-treatment associated with prognosis for adults with depression in primary care?

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

Cost-Effectiveness of Different Formats for Delivery of Cognitive Behavioral Therapy for Depression: A Systematic Review Based Economic Model.

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

Reference-based multiple imputation for missing data sensitivity analyses in trial-based cost-effectiveness analysis.

Missing data are a common issue in cost-effectiveness analysis (CEA) alongside randomised trials and are often addressed assuming the data are 'missing at random'. However, this assumption is often questionable, and sensitivity analyses are required to assess the implications of departures from missing at random. Reference-based multiple imputation provides an attractive approach for conducting such sensitivity analyses, because missing data assumptions are framed in an intuitive way by making reference to other trial arms. For example, a plausible not at random mechanism in a placebo-controlled trial would be to assume that participants in the experimental arm who dropped out stop taking their treatment and have similar outcomes to those in the placebo arm. Drawing on the increasing use of this approach in other areas, this paper aims to extend and illustrate the reference-based multiple imputation approach in CEA. It introduces the principles of reference-based imputation and proposes an extension to the CEA context. The method is illustrated in the CEA of the CoBalT trial evaluating cognitive behavioural therapy for treatment-resistant depression. Stata code is provided. We find that reference-based multiple imputation provides a relevant and accessible framework for assessing the robustness of CEA conclusions to different missing data assumptions.

An expert consensus on the most effective components of cognitive behavioural therapy for adults with depression: a modified Delphi study.

Designing new approaches to delivering cognitive behavioural therapy (CBT) requires an understanding of the key components. This study aimed to establish an expert consensus on the effective components of CBT for depressed adults. An international panel of 120 CBT experts was invited to participate in a modified Delphi study. Thirty-two experts participated in round 1; 21 also provided data in round 2. In round 1, experts rated the effectiveness of 35 content and process components. A priori rules identified components carried forward to round 2, in which experts re-rated items and final consensus items were identified. Consensus was achieved for nine content components (ensuring understanding; developing and maintaining a good therapeutic alliance; explaining the rationale for CBT; eliciting feedback; identifying and challenging avoidant behaviour; activity monitoring; undertaking an initial assessment; relapse prevention methods; homework assignments); and three process components (ensuring therapist competence; scheduling sessions flexibly; scheduling sessions for 45-60 mins). Five of the twelve components identified were generic therapeutic competences rather than specific CBT items. There was less agreement about the effectiveness of cognitive components of CBT. This is an important first step in the development of novel approaches to delivering CBT that may increase access to treatment for patients.

The process and delivery of CBT for depression in adults: a systematic review and network meta-analysis.

Cognitive-behavioural therapy (CBT) is an effective treatment for depressed adults. CBT interventions are complex, as they include multiple content components and can be delivered in different ways. We compared the effectiveness of different types of therapy, different components and combinations of components and aspects of delivery used in CBT interventions for adult depression. We conducted a systematic review of randomised controlled trials in adults with a primary diagnosis of depression, which included a CBT intervention. Outcomes were pooled using a component-level network meta-analysis. Our primary analysis classified interventions according to the type of therapy and delivery mode. We also fitted more advanced models to examine the effectiveness of each content component or combination of components. We included 91 studies and found strong evidence that CBT interventions yielded a larger short-term decrease in depression scores compared to treatment-as-usual, with a standardised difference in mean change of -1.11 (95% credible interval -1.62 to -0.60) for face-to-face CBT, -1.06 (-2.05 to -0.08) for hybrid CBT, and -0.59 (-1.20 to 0.02) for multimedia CBT, whereas wait list control showed a detrimental effect of 0.72 (0.09 to 1.35). We found no evidence of specific effects of any content components or combinations of components. Technology is increasingly used in the context of CBT interventions for depression. Multimedia and hybrid CBT might be as effective as face-to-face CBT, although results need to be interpreted cautiously. The effectiveness of specific combinations of content components and delivery formats remain unclear. Wait list controls should be avoided if possible.

Pharmacological interventions for treatment-resistant depression in adults.

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

Is screen time associated with anxiety or depression in young people? Results from a UK birth cohort.

BACKGROUND: There is limited and conflicting evidence for associations between use of screen-based technology and anxiety and depression in young people. We examined associations between screen time measured at 16 years and anxiety and depression at 18. METHODS: Participants (n = 14,665; complete cases n = 1869) were from the Avon Longitudinal Study of Parents and Children, a UK-based prospective cohort study. We assessed associations between various types of screen time (watching television, using a computer, and texting, all measured via questionnaire at 16y), both on weekdays and at weekends, and anxiety and depression (measured via the Revised Clinical Interview Schedule at 18y). Using ordinal logistic regression, we adjusted for multiple confounders, particularly focussing on activities that might have been replaced by screen time (for example exercising or playing outdoors). RESULTS: More time spent using a computer on weekdays was associated with a small increased risk of anxiety (OR for 1-2 h = 1.17, 95% CI: 1.01 to 1.35; OR for 3+ hours = 1.30, 95% CI: 1.10 to 1.55, both compared to < 1 h, p for linear trend = 0.003). We found a similar association between computer use at weekends and anxiety (OR for 1-2 h = 1.17, 95% CI: 0.94 to 1.46; OR for 3+ hours = 1.28, 95% CI: 1.03 to 1.48, p for linear trend = 0.03). Greater time spent using a computer on weekend days only was associated with a small increased risk in depression (OR for 1-2 h = 1.12, 95% CI: 0.93 to 1.35; OR for 3+ hours = 1.35, 95% CI: 1.10 to 1.65, p for linear trend = 0.003). Adjusting for time spent alone attenuated effects for anxiety but not depression. There was little evidence for associations with texting or watching television. CONCLUSIONS: We found associations between increased screen time, particularly computer use, and a small increased risk of anxiety and depression. Time spent alone was found to attenuate some associations, and further research should explore this.

Materials used to support cognitive behavioural therapy for depression: a survey of therapists' clinical practice and views.

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

Psychological therapies for treatment-resistant depression in adults.

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