Feasibility study of eye movement desensitisation and reprocessing (EMDR) in people with an at-risk mental state (ARMS) for psychosis:study protocol

Introduction Trauma can play an important role in the development of psychosis, yet no studies have investigated whether a trauma-focused psychological therapy could prevent the onset of psychosis in people at high risk of developing this condition. This study aims to establish whether it would be feasible to conduct a multicentre randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of eye movement desensitisation and reprocessing (EMDR) therapy to prevent the onset of psychosis in people with an at-risk mental state (ARMS). Methods/analysis This is a single-arm trial with a nested qualitative study where all participants (target n=20) will be offered EMDR. Eligible participants are those who meet criteria for ARMS; have experienced a traumatic event before the onset of ARMS symptomatology; and have at least one symptom of post-traumatic stress disorder (PTSD). Participants will be followed up at 4, 8 and 12 months after the baseline assessment. The primary outcome measure is transition to psychosis, and secondary outcome measures include severity of psychotic symptoms, PTSD, depression, anxiety, impaired functioning, health status and resource use. The analysis will aim to establish the rates of recruitment and retention for a large-scale RCT. Interviews with therapists and patients will explore their views of the study and their experiences of delivering or receiving EMDR. Ethics and dissemination This protocol has been approved by the South West-Cornwall and Plymouth Research Ethics Committee (Reference 18/SW/0037). Findings will be disseminated through journal publications, conference presentations and meetings with service users, their families, mental health professionals and commissioners. Trial registration number ISRCTN31976295

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

Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial

Background: Cognitive behavioural therapy (CBT) is an effective treatment for people whose depression has not responded to antidepressants. However, the long-term outcome is unknown. In a long-term follow-up of the CoBalT trial, we examined the clinical and cost-effectiveness of cognitive behavioural therapy as an adjunct to usual care that included medication over 3–5 years in primary care patients with treatment-resistant depression. Methods: CoBalT was a randomised controlled trial done across 73 general practices in three UK centres. CoBalT recruited patients aged 18–75 years who had adhered to antidepressants for at least 6 weeks and had substantial depressive symptoms (Beck Depression Inventory [BDI-II] score ≥14 and met ICD-10 depression criteria). Participants were randomly assigned using a computer generated code, to receive either usual care or CBT in addition to usual care. Patients eligible for the long-term follow-up were those who had not withdrawn by the 12 month follow-up and had given their consent to being re-contacted. Those willing to participate were asked to return the postal questionnaire to the research team. One postal reminder was sent and non-responders were contacted by telephone to complete a brief questionnaire. Data were also collected from general practitioner notes. Follow-up took place at a variable interval after randomisation (3–5 years). The primary outcome was self-report of depressive symptoms assessed by BDI-II score (range 0–63), analysed by intention to treat. Cost-utility analysis compared health and social care costs with quality-adjusted life-years (QALYs). This study is registered with isrctn.com, number ISRCTN38231611. Findings: Between Nov 4, 2008, and Sept 30, 2010, 469 eligible participants were randomised into the CoBalT study. Of these, 248 individuals completed a long-term follow-up questionnaire and provided data for the primary outcome (136 in the intervention group vs 112 in the usual care group). At follow-up (median 45·5 months [IQR 42·5–51·1]), the intervention group had a mean BDI-II score of 19·2 (SD 13·8) compared with a mean BDI-II score of 23·4 (SD 13·2) for the usual care group (repeated measures analysis over the 46 months: difference in means −4·7 [95% CI −6·4 to −3·0, p<0·001]). Follow-up was, on average, 40 months after therapy ended. The average annual cost of trial CBT per participant was £343 (SD 129). The incremental cost-effectiveness ratio was £5374 per QALY gain. This represented a 92% probability of being cost effective at the National Institute for Health and Care Excellence QALY threshold of £20 000. Interpretation: CBT as an adjunct to usual care that includes antidepressants is clinically effective and cost effective over the long-term for individuals whose depression has not responded to pharmacotherapy. In view of this robust evidence of long-term effectiveness and the fact that the intervention represented good value-for-money, clinicians should discuss referral for CBT with all those for whom antidepressants are not effective

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

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

Design Considerations for the Integrated Delivery of Cognitive Behavioral Therapy for Depression:A User-Centered Design Study

Background: Adherence to computerized Cognitive Behavioral Therapy (cCBT) programs in real world settings can be poor and, in the absence of therapist support, effects are modest and short-term. Moreover, because cCBT systems tend towards limited support and thus low-intensity treatment, they are typically most appropriate for people with mild to moderate difficulties. Blended therapy, i.e. combining direct contact with a therapist with cCBT or psychoeducational materials, has been identified as one possible approach to addressing these limitations and widening access to individual CBT for depression. To date research on blended therapy systems is quite limited, particularly in comparison to more widely explored cCBT systems. While the design space and range of potential configurations for blended systems is large, only a small portion of this design space has been investigated to date. Objective: First, to explore patients’ and therapists’ views on using a system for the delivery of individual treatment for depression that integrates face-to-face contact with a therapist with access to online resources and with synchronous online therapy sessions that allow collaborative worksheet editing. Second, to establish design requirements and thus key design considerations for blended systems that further integrate different modes of communication. In particular, we were interested in exploring barriers relating to remote therapy and engagement with this type of treatment, understanding patients’ expectations of technology, and understanding therapists’ experiences of and attitudes towards the use of technology to support their work. Methods: We conducted design workshops and prototype testing sessions with 18 people who had received CBT for depression in the past, and qualitative interviews and role-play sessions with 12 CBT therapists experienced in the treatment of depression. Results: Workshops and prototyping sessions with people who had received CBT identified three important requirements for an integrated platform delivering CBT therapy for depression: 1) features that help to overcome depression-related barriers, 2) features that support engagement, and 3) features that reinforce learning and support the development of new skills. Research with therapists highlighted the importance of the therapist and client working together, the impact of technology on therapists’ workflow and workload, challenges and opportunities related to the use of online resources, and the potential of technology to support patient engagement. We use these findings to inform 12 design considerations for developing integrated therapy systems. Conclusions: To meet clients’ and therapists’ needs, integrated systems need to help retain the personal connection, support both therapist- and patient-led activities, provide access to materials and the ability to monitor progress. However, developers of such systems should be mindful of their capacity to disrupt current work practices and increase therapists’ workload. Future work should evaluate the impact of integrated systems on delivering and receiving therapy in a real-world context

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

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