Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1.

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.

Design Considerations for the Integrated Delivery of Cognitive Behavioral Therapy for Depression: 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 toward limited support and thus low-intensity treatment, they are typically most appropriate for people experiencing mild to moderate mental health difficulties. Blended therapy, that is, combining direct therapist contact with cCBT or psychoeducational materials, has been identified as one possible approach to address these limitations and widen access to individual CBT for depression. Building on the initial success of blended therapy, we explore an integrated approach that seeks to seamlessly combine face-to-face contact, electronic contact, and between-session activities. Integration also considers how the technology can support therapists' workflow and integrate with broader health care systems. The ultimate aim is to provide a structure within which therapists can deliver high-intensity treatments, while also greatly reducing face-to-face contact. OBJECTIVE: The research aimed to explore patients' and therapists' views on using a system for the delivery of individual treatment for depression that integrates face-to-face therapist contact with access to online resources and with synchronous online therapy sessions that allow collaborative exercises, and to establish design requirements and thus key design considerations for integrated systems that more seamlessly combine different modes of communication. METHODS: We conducted a series of four user-centered design studies. This included four design workshops and seven prototype testing sessions with 18 people who had received CBT for depression in the past, and 11 qualitative interviews and three role-play sessions with 12 CBT therapists experienced in the treatment of depression. Studies took place between July and December 2017 in Bristol, United Kingdom. RESULTS: Workshops and prototyping sessions with people who had received CBT identified three important requirements for integrated platforms delivering CBT therapy for depression as follows: (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, and 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 research should evaluate the impact of integrated systems on patients and therapists in a real-world context.

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.

Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT.

BACKGROUND: Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant. OBJECTIVES: To investigate whether or not combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment-resistant depression (TRD). DESIGN: The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual. SETTING: Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele. PARTICIPANTS: Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression. INTERVENTIONS: Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation. MAIN OUTCOME MEASURES: The primary outcome was depression symptoms at 12 weeks post randomisation compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients' views and experiences of managing depression and GPs' views on prescribing a second antidepressant. RESULTS: There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference -1.83 points, 95% confidence interval (CI) -3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: -0.85 points, 95% CI -3.12 to 1.43 points; 12 months: 0.17 points, 95% CI -2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants). CONCLUSIONS: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant. LIMITATIONS: Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult. FUTURE WORK: Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.

User Experience of Cognitive Behavioral Therapy Apps for Depression: An Analysis of App Functionality and User Reviews.

BACKGROUND: Hundreds of mental health apps are available to the general public. With increasing pressures on health care systems, they offer a potential way for people to support their mental health and well-being. However, although many are highly rated by users, few are evidence-based. Equally, our understanding of what makes apps engaging and valuable to users is limited. OBJECTIVE: The aim of this paper was to analyze functionality and user opinions of mobile apps purporting to support cognitive behavioral therapy for depression and to explore key factors that have an impact on user experience and support engagement. METHODS: We systematically identified apps described as being based on cognitive behavioral therapy for depression. We then conducted 2 studies. In the first, we analyzed the therapeutic functionality of apps. This corroborated existing work on apps' fidelity to cognitive behavioral therapy theory, but we also extended prior work by examining features designed to support user engagement. Engagement features found in cognitive behavioral therapy apps for depression were compared with those found in a larger group of apps that support mental well-being in a more general sense. Our second study involved a more detailed examination of user experience, through a thematic analysis of publicly available user reviews of cognitive behavioral therapy apps for depression. RESULTS: We identified 31 apps that purport to be based on cognitive behavioral therapy for depression. Functionality analysis (study 1) showed that they offered an eclectic mix of features, including many not based on cognitive behavioral therapy practice. Cognitive behavioral therapy apps used less varied engagement features compared with 253 other mental well-being apps. The analysis of 1287 user reviews of cognitive behavioral therapy apps for depression (study 2) showed that apps are used in a wide range of contexts, both replacing and augmenting therapy, and allowing users to play an active role in supporting their mental health and well-being. Users, including health professionals, valued and used apps that incorporated both core cognitive behavioral therapy and non-cognitive behavioral therapy elements, but concerns were also expressed regarding the unsupervised use of apps. Positivity was seen as important to engagement, for example, in the context of automatic thoughts, users expressed a preference to capture not just negative but also positive ones. Privacy, security, and trust were crucial to the user experience. CONCLUSIONS: Cognitive behavioral therapy apps for depression need to improve with respect to incorporating evidence-based cognitive behavioral therapy elements. Equally, a positive user experience is dependent on other design factors, including consideration of varying contexts of use. App designers should be able to clearly identify the therapeutic basis of their apps, but they should also draw on evidence-based strategies to support a positive and engaging user experience. The most effective apps are likely to strike a balance between evidence-based cognitive behavioral therapy strategies and evidence-based design strategies, including the possibility of eclectic therapeutic techniques.

Telephone-supported computerised cognitive-behavioural therapy: REEACT-2 large-scale pragmatic randomised controlled trial.

BackgroundComputerised cognitive-behavioural therapy (cCBT) for depression has the potential to be efficient therapy but engagement is poor in primary care trials.AimsWe tested the benefits of adding telephone support to cCBT.MethodWe compared telephone-facilitated cCBT (MoodGYM) (n = 187) to minimally supported cCBT (MoodGYM) (n = 182) in a pragmatic randomised trial (trial registration: ISRCTN55310481). Outcomes were depression severity (Patient Health Questionnaire (PHQ)-9), anxiety (Generalized Anxiety Disorder Questionnaire (GAD)-7) and somatoform complaints (PHQ-15) at 4 and 12 months.ResultsUse of cCBT increased by a factor of between 1.5 and 2 with telephone facilitation. At 4 months PHQ-9 scores were 1.9 points lower (95% CI 0.5-3.3) for telephone-supported cCBT. At 12 months, the results were no longer statistically significant (0.9 PHQ-9 points, 95% CI -0.5 to 2.3). There was improvement in anxiety scores and for somatic complaints.ConclusionsTelephone facilitation of cCBT improves engagement and expedites depression improvement. The effect was small to moderate and comparable with other low-intensity psychological interventions.

The second Randomised Evaluation of the Effectiveness, cost-effectiveness and Acceptability of Computerised Therapy (REEACT-2) trial: does the provision of telephone support enhance the effectiveness of computer-delivered cognitive behaviour therapy? A randomised controlled trial.

BACKGROUND: Computerised cognitive behaviour therapy (cCBT) is an efficient form of therapy potentially improving access to psychological care. Indirect evidence suggests that the uptake and effectiveness of cCBT can be increased if facilitated by telephone, but this is not routinely offered in the NHS. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of telephone-facilitated free-to-use cCBT [e.g. MoodGYM (National Institute for Mental Health Research, Australian National University, Canberra, ACT, Australia)] with minimally supported cCBT. DESIGN: This study was a multisite, pragmatic, open, two-arm, parallel-group randomised controlled trial with a concurrent economic evaluation. SETTING: Participants were recruited from GP practices in Bristol, Manchester, Sheffield, Hull and the north-east of England. PARTICIPANTS: Potential participants were eligible to participate in the trial if they were adults with depression scoring ≥ 10 on the Patient Health Questionnaire-9 (PHQ-9). INTERVENTIONS: Participants were randomised using a computer-generated random number sequence to receive minimally supported cCBT or telephone-facilitated cCBT. Participants continued with usual general practitioner care. MAIN OUTCOME MEASURES: The primary outcome was self-reported symptoms of depression, as assessed by the PHQ-9 at 4 months post randomisation. SECONDARY OUTCOMES: Secondary outcomes were depression at 12 months and anxiety, somatoform complaints, health utility (as assessed by the European Quality of Life-5 Dimensions questionnaire) and resource use at 4 and 12 months. RESULTS: Clinical effectiveness: 182 participants were randomised to minimally supported cCBT and 187 participants to telephone-facilitated cCBT. There was a difference in the severity of depression at 4 and 12 months, with lower levels in the telephone-facilitated group. The odds of no longer being depressed (defined as a PHQ-9 score of < 10) at 4 months were twice as high in the telephone-facilitated cCBT group [odds ratio (OR) 2.05, 95% confidence interval (CI) 1.23 to 3.42]. The benefit of telephone-facilitated cCBT was no longer significant at 12 months (OR 1.63, 95% CI 0.98 to 2.71). At 4 months the between-group difference in PHQ-9 scores was 1.9 (95% CI 0.5 to 3.3). At 12 months the results still favoured telephone-facilitated cCBT but were no longer statistically significant, with a difference in PHQ-9 score of 0.9 (95% CI -0.5 to 2.3). When considering the whole follow-up period, telephone-facilitated cCBT was asssociated with significantly lower PHQ-9 scores than minimally supported cCBT (mean difference -1.41, 95% CI -2.63 to -0.17; p = 0.025). There was a significant improvement in anxiety scores over the trial period (between-group difference 1.1, 95% CI 0.1 to 2.3; p = 0.037). In the case of somatic complaints (assessed using the Patient Health Questionnaire-15), there was a borderline statistically significant difference over the trial period (between-group difference 1.1, 95% CI 0.0 to 1.8; p = 0.051). There were gains in quality-adjusted life-years at reduced cost when telephone facilitation was added to MoodGYM. However, the results were subject to uncertainty. CONCLUSIONS: The results showed short-term benefits from the addition of telephone facilitation to cCBT. The effect was small to moderate and comparable with that of other primary care psychological interventions. Telephone facilitation should be considered when offering cCBT for depression. LIMITATIONS: Participants' depression was assessed with the PHQ-9, cCBT use was quite low and there was a slightly greater than anticipated loss to follow-up. FUTURE RESEARCH RECOMMENDATIONS: Improve the acceptability of cCBT and its capacity to address coexisting disorders. Large-scale pragmatic trials of cCBT with bibliotherapy and telephone-based interventions are required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55310481. 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. 20, No. 89. See the NIHR Journals Library website for further project information.

Mirtazapine added to selective serotonin reuptake inhibitors for treatment-resistant depression in primary care (MIR trial): study protocol for a randomised controlled trial.

BACKGROUND: People with depression are usually managed in primary care and antidepressants are often the first-line treatment, but only one third of patients respond fully to a single antidepressant. This paper describes the protocol for a randomised controlled trial (MIR) to investigate the extent to which the addition of the antidepressant mirtazapine is effective in reducing the symptoms of depression compared with placebo in patients who are still depressed after they have been treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI) for at least 6 weeks in primary care. METHODS/DESIGN: MIR is a two-parallel group, multi-centre, pragmatic, placebo controlled, randomised trial with allocation at the level of the individual. Eligible participants are those who: are aged 18 years or older; are currently taking an SSRI/SNRI antidepressant (for at least 6 weeks at an adequate dose); score ≥ 14 on the Beck Depression Inventory (BDI-II); have adhered to their medication; and meet ICD-10 criteria for depression (assessed using the Clinical Interview Schedule-Revised version). Participants who give written, informed consent, will be randomised to receive either oral mirtazapine or matched placebo, starting at 15 mg daily for 2 weeks and increasing to 30 mg daily thereafter, for up to 12 months (to be taken in addition to their usual antidepressant). Participants, their GPs, and the research team will all be blind to the allocation. The primary outcome will be depression symptoms at 12 weeks post randomisation, measured as a continuous variable using the BDI-II. Secondary outcomes (measured at 12, 24 and 52 weeks) include: response (reduction in depressive symptoms (BDI-II score) of at least 50% compared to baseline); remission of depression symptoms (BDI-II <10); change in anxiety symptoms; adverse effects; quality of life; adherence to antidepressant medication; health and social care use, time off work and cost-effectiveness. All outcomes will be analysed on an intention-to-treat basis. A qualitative study will explore patients' views and experiences of either taking two antidepressants, or an antidepressant and a placebo; and GPs' views on prescribing a second antidepressant in this patient group. DISCUSSION: The MIR trial will provide evidence on the clinical and cost-effectiveness of mirtazapine as an adjunct to SSRI/SNRI antidepressants for patients in primary care who have not responded to monotherapy. TRIAL REGISTRATION: EudraCT Number: 2012-000090-23 (Registered January 2012); ISRCTN06653773 (Registered September 2012).

A randomised controlled trial of computerised cognitive behaviour therapy for the treatment of depression in primary care: the Randomised Evaluation of the Effectiveness and Acceptability of Computerised Therapy (REEACT) trial.

BACKGROUND: Computerised cognitive behaviour therapy (cCBT) has been developed as an efficient form of therapy delivery with the potential to enhance access to psychological care. Independent research is needed which examines both the clinical effectiveness and cost-effectiveness of cCBT over the short and longer term. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of cCBT as an adjunct to usual general practitioner (GP) care against usual GP care alone, for a free-to-use cCBT program (MoodGYM; National Institute for Mental Health Research, Australian National University, Canberra, Australia) and a commercial pay-to-use cCBT program (Beating the Blues(®); Ultrasis, London, UK) for adults with depression, and to determine the acceptability of cCBT and the experiences of users. DESIGN: A pragmatic, multicentre, three-armed, parallel, randomised controlled trial (RCT) with concurrent economic and qualitative evaluations. Simple randomisation was used. Participants and researchers were not blind to treatment allocation. SETTING: Primary care in England. PARTICIPANTS: Adults with depression who scored ≥ 10 on the Patient Health Questionnaire-9 (PHQ-9). INTERVENTIONS: Participants who were randomised to either of the two intervention groups received cCBT (Beating the Blues or MoodGYM) in addition to usual GP care. Participants who were randomised to the control group were offered usual GP care. MAIN OUTCOME MEASURES: The primary outcome was depression at 4 months (PHQ-9). Secondary outcomes were depression at 12 and 24 months; measures of mental health and health-related quality of life at 4, 12 and 24 months; treatment preference; and the acceptability of cCBT and experiences of users. RESULTS: Clinical effectiveness: 210 patients were randomised to Beating the Blues, 242 patients were randomised to MoodGYM and 239 patients were randomised to usual GP care (total 691). There was no difference in the primary outcome (depression measured at 4 months) either between Beating the Blues and usual GP care [odds ratio (OR) 1.19, 95% confidence interval (CI) 0.75 to 1.88] or between MoodGYM and usual GP care (OR 0.98, 95% CI 0.62 to 1.56). There was no overall difference across all time points for either intervention compared with usual GP care in a mixed model (Beating the Blues versus usual GP care, p = 0.96; and MoodGYM versus usual GP care, p = 0.11). However, a small but statistically significant difference between MoodGYM and usual GP care at 12 months was found (OR 0.56, 95% CI 0.34 to 0.93). Free-to-use cCBT (MoodGYM) was not inferior to pay-to-use cCBT (Beating the Blues) (OR 0.91, 90% CI 0.62 to 1.34; p = 0.69). There were no consistent benefits of either intervention when secondary outcomes were examined. There were no serious adverse events thought likely to be related to the trial intervention. Despite the provision of regular technical telephone support, there was low uptake of the cCBT programs. Cost-effectiveness: cost-effectiveness analyses suggest that neither Beating the Blues nor MoodGYM appeared cost-effective compared with usual GP care alone. Qualitative evaluation: participants were often demotivated to access the computer programs, by reason of depression. Some expressed the view that a greater level of therapeutic input would be needed to promote engagement. CONCLUSIONS: The benefits that have previously been observed in developer-led trials were not found in this large pragmatic RCT. The benefits of cCBT when added to routine primary care were minimal, and uptake of this mode of therapy was relatively low. There remains a clinical and economic need for effective low-intensity psychological treatments for depression with improved patient engagement. TRIAL REGISTRATION: This trial is registered as ISRCTN91947481. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme.

Computerised cognitive behaviour therapy (cCBT) as treatment for depression in primary care (REEACT trial): large scale pragmatic randomised controlled trial.

STUDY QUESTION: How effective is supported computerised cognitive behaviour therapy (cCBT) as an adjunct to usual primary care for adults with depression? METHODS: This was a pragmatic, multicentre, three arm, parallel randomised controlled trial with simple randomisation. Treatment allocation was not blinded. Participants were adults with symptoms of depression (score ≥ 10 on nine item patient health questionnaire, PHQ-9) who were randomised to receive a commercially produced cCBT programme ("Beating the Blues") or a free to use cCBT programme (MoodGYM) in addition to usual GP care. Participants were supported and encouraged to complete the programme via weekly telephone calls. Control participants were offered usual GP care, with no constraints on the range of treatments that could be accessed. The primary outcome was severity of depression assessed with the PHQ-9 at four months. Secondary outcomes included health related quality of life (measured by SF-36) and psychological wellbeing (measured by CORE-OM) at four, 12, and 24 months and depression at 12 and 24 months. STUDY ANSWER AND LIMITATIONS: Participants offered commercial or free to use cCBT experienced no additional improvement in depression compared with usual GP care at four months (odds ratio 1.19 (95% confidence interval 0.75 to 1.88) for Beating the Blues v usual GP care; 0.98 (0.62 to 1.56) for MoodGYM v usual GP care). There was no evidence of an overall difference between either programme compared with usual GP care (0.99 (0.57 to 1.70) and 0.68 (0.42 to 1.10), respectively) at any time point. Commercially provided cCBT conferred no additional benefit over free to use cCBT or usual GP care at any follow-up point. Uptake and use of cCBT was low, despite regular telephone support. Nearly a quarter of participants (24%) had dropped out by four months. The study did not have enough power to detect small differences so these cannot be ruled out. Findings cannot be generalised to cCBT offered with a much higher level of guidance and support. WHAT THIS STUDY ADDS: Supported cCBT does not substantially improve depression outcomes compared with usual GP care alone. In this study, neither a commercially available nor free to use computerised CBT intervention was superior to usual GP care. FUNDING, COMPETING INTERESTS, DATA SHARING: Commissioned and funded by the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project No 06/43/05). The authors have no competing interests. Requests for patient level data will be considered by the REEACT trial management groupTrial registration Current Controlled Trials ISRCTN91947481.

Severity of depression and response to antidepressants: GENPOD randomised controlled trial.

BACKGROUND: Antidepressant prescribing is widespread. Nonetheless, response to antidepressants is variable. If it was possible to predict response to medication and thus tailor treatment accordingly, this would not only improve patient outcomes but may also have economic benefits. AIMS: To test the hypothesis that individuals with more severe depression would benefit more from noradrenaline reuptake inhibitors (NARIs) than selective serotonin reuptake inhibitors (SSRIs) compared with individuals with less severe depression. METHOD: Individuals recruited from UK primary care who met ICD-10 criteria for a depressive episode and scored 15 or more on the Beck Depression Inventory (BDI) were randomised to either an SSRI (citalopram 20 mg daily) or a NARI (reboxetine 4 mg twice daily). Randomisation was by means of a remote automated telephone system. The main outcome was depressive symptoms measured by the BDI total score 6 weeks after randomisation. ( TRIAL REGISTRATION: ISRCTN31345163.) RESULTS: In total, 601 participants were randomised (citalopram: n = 298, reboxetine: n = 303). Ninety-one per cent were followed up at 6 weeks (citalopram: n = 274, reboxetine: n = 272). There was little evidence to support an interaction between treatment and severity of depression (interaction term: 0.02, 95% CI -0.59 to 0.62, P = 0.96). Adjustment for potential confounders (age, gender, employment status, history of depression, number of life events and social support) did not affect the findings (interaction term: 0.06, 95% CI -0.54 to 0.66, P = 0.85). CONCLUSIONS: Treatment with NARIs does not confer any advantage over SSRI treatment for outcome in those with more severe depressive illness presenting in primary care.

Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial.

BACKGROUND: Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters. We wished to investigate whether genetic variation could be used to target or personalise treatment, in a comparison of selective serotonin reuptake inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs). AIMS: To test the hypothesis that patients homozygous for the long (insertion) polymorphism of the serotonin transporter (5-HTTLPR) have an increased response to SSRI antidepressants but not to NARI antidepressants. METHOD: In an individually randomised, parallel-group controlled trial, people meeting criteria for a depressive episode who were referred by their general practitioner were randomised to receive either citalopram (an SSRI) or reboxetine (an NARI). Randomisation was by means of a remote automated system accessed by telephone. The main outcome was depressive symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks after randomisation. The trial was registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN31345163). RESULTS: Altogether 298 participants were randomised to receive citalopram and 303 were randomised to reboxetine. At 6 weeks follow-up, complete data were available for 258 participants taking citalopram and 262 taking reboxetine. We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment. The interaction term for BDI score at 6 weeks was 0.50 (95% CI -2.04 to 3.03, P = 0.70), which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype. CONCLUSIONS: It is unlikely that the 5-HTTLPR polymorphism alone will be clinically useful in predicting response to antidepressants in people with depression.

GENetic and clinical predictors of treatment response in depression: the GenPod randomised trial protocol.

BACKGROUND: The most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin (Selective Serotonin Reuptake Inhibitors - SSRIs) and noradrenaline (Noradrenaline Reuptake Inhibitors - NaRIs) into the presynaptic terminal. There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action. Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs, there are patients who respond to one class of compounds and not another. This suggests that treatment response could be predicted by genetic and/or clinical characteristics. Firstly, this study aims to investigate the influence of a polymorphism (SLC6A4) in the 5HT transporter in altering response to SSRI medication. Secondly, the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs. METHODS/DESIGN: The GenPod trial is a multi-centre randomised controlled trial. GPs referred patients aged between 18-74 years presenting with a new episode of depression, who did not have any medical contraindications to antidepressant medication and who had no history of psychosis or alcohol/substance abuse. Patients were interviewed to ascertain their suitability for the study. Eligible participants (with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory (BDI) score > 14) were randomised to receive one of two antidepressant treatments, either the SSRI Citalopram or the NaRI Reboxetine, stratified according to severity. The final number randomised to the trial was 601. Follow-up assessments took place at 2, 6 and 12 weeks following randomisation. Primary outcome was measured at 6 weeks by the BDI. Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments. DISCUSSION: The results of the trial will provide information about targeting antidepressant treatment for individual patients; in turn this may increase prescribing efficacy, thereby speeding recovery and reducing the cost to the NHS. It will also help to understand the different roles that noradrenaline and serotonin might play in the biology of depression. The trial is expected to report in the autumn of 2008. TRIAL REGISTRATION: ISRCTN 31345163.