Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Cognitive Behavior Therapy for Depression From an Evolutionary Perspective.

Evolutionary medicine attempts to solve a problem with which traditional medicine has struggled historically; how do we distinguish between diseased states and "healthy" responses to disease states? Fever and diarrhea represent classic examples of evolved adaptations that increase the likelihood of survival in response to the presence of pathogens in the body. Whereas, the severe mental disorders like psychotic mania or the schizophrenias may involve true "disease" states best treated pharmacologically, most non-psychotic "disorders" that revolve around negative affects like depression or anxiety are likely adaptations that evolved to serve a function that increased inclusive fitness in our ancestral past. What this likely means is that the proximal mechanisms underlying the non-psychotic "disorders" are "species typical" and neither diseases nor disorders. Rather, they are coordinated "whole body" responses that prepare the individual to respond in a maximally functional fashion to the variety of different challenges that our ancestors faced. A case can be made that depression evolved to facilitate a deliberate cognitive style (rumination) in response to complex (often social) problems. What this further suggests is that those interventions that best facilitate the functions that those adaptations evolved to serve (such as rumination) are likely to be preferred over those like medications that simply anesthetize the distress. We consider the mechanisms that evolved to generate depression and the processes utilized in cognitive behavior therapy to facilitate those functions from an adaptationist evolutionary perspective.

Cost and Outcome of BehaviouRal Activation (COBRA): a randomised controlled trial of behavioural activation versus cognitive-behavioural therapy for depression.

BACKGROUND: Depression is a common, debilitating and costly disorder. The best-evidenced psychological therapy - cognitive-behavioural therapy (CBT) - is complex and costly. A simpler therapy, behavioural activation (BA), may be an effective alternative. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of BA compared with CBT for depressed adults at 12 and 18 months' follow-up, and to investigate the processes of treatments. DESIGN: Randomised controlled, non-inferiority trial stratified by depression severity, antidepressant use and recruitment site, with embedded process evaluation; and randomisation by remote computer-generated allocation. SETTING: Three community mental health services in England. PARTICIPANTS: Adults aged ≥ 18 years with major depressive disorder (MDD) recruited from primary care and psychological therapy services. INTERVENTIONS: BA delivered by NHS junior mental health workers (MHWs); CBT by NHS psychological therapists. OUTCOMES: Primary: depression severity (as measured via the Patient Health Questionnaire-9; PHQ-9) at 12 months. Secondary: MDD status; number of depression-free days; anxiety (as measured via the Generalised Anxiety Disorder-7); health-related quality of life (as measured via the Short Form questionnaire-36 items) at 6, 12 and 18 months; and PHQ-9 at 6 and 18 months, all collected by assessors blinded to treatment allocation. Non-inferiority margin was 1.9 PHQ-9 points. We undertook intention-to-treat (ITT) and per protocol (PP) analyses. We explored cost-effectiveness by collecting direct treatment and other health- and social-care costs and calculating quality-adjusted life-years (QALYs) using the EuroQol-5 Dimensions, three-level version, at 18 months. RESULTS: We recruited 440 participants (BA, n = 221; CBT, n = 219); 175 (79%) BA and 189 (86%) CBT participants provided ITT data and 135 (61%) BA and 151 (69%) CBT participants provided PP data. At 12 months we found that BA was non-inferior to CBT {ITT: CBT 8.4 PHQ-9 points [standard deviation (SD) 7.5 PHQ-9 points], BA 8.4 PHQ-9 points (SD 7.0 PHQ-9 points), mean difference 0.1 PHQ-9 points, 95% confidence interval (CI) -1.3 to 1.5 PHQ-9 points, p = 0.89; PP: CBT 7.9 PHQ-9 points (SD 7.3 PHQ-9 points), BA 7.8 PHQ-9 points (SD 6.5 PHQ-9 points), mean difference 0.0 PHQ-9 points, 95% CI -1.5 to 1.6 PHQ-9 points, p = 0.99}. We found no differences in secondary outcomes. We found a significant difference in mean intervention costs (BA, £975; CBT, £1235; p < 0.001), but no differences in non-intervention (hospital, community health, social care and medication costs) or total (non-intervention plus intervention) costs. Costs were lower and QALY outcomes better in the BA group, generating an incremental cost-effectiveness ratio of -£6865. The probability of BA being cost-effective compared with CBT was almost 80% at the National Institute for Health and Care Excellence's preferred willingness-to-pay threshold of £20,000-30,000 per QALY. There were no trial-related adverse events. LIMITATIONS: In this pragmatic trial many depressed participants in both groups were also taking antidepressant medication, although most had been doing so for a considerable time before entering the trial. Around one-third of participants chose not to complete a PP dose of treatment, a finding common in both psychotherapy trials and routine practice. CONCLUSIONS: We found that BA is as effective as CBT, more cost-effective and can be delivered by MHWs with no professional training in psychological therapies. FUTURE WORK: Settings and countries with a paucity of professionally qualified psychological therapists, might choose to investigate the delivery of effective psychological therapy for depression without the need to develop an extensive and costly professional infrastructure. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27473954. 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. 21, No. 46. See the NIHR Journals Library website for further project information.

Comparative efficacy of psychological therapies for improving mental health and daily functioning in irritable bowel syndrome: A systematic review and meta-analysis.

Previous meta-analyses have shown that psychotherapy improves gastrointestinal symptoms in adults with irritable bowel syndrome (IBS); however, the impact on functioning in daily activities is unknown. Meta-analysis was used to estimate the effect of psychotherapy on mental health and daily functioning in adults with IBS. An extensive literature search located 28 eligible randomized controlled trials (RCTs) providing outcome data for mental health and 18 RCTs providing data for daily functioning. Compared to a mixed group of control conditions, psychotherapy produced significantly greater improvements to mental health (d-=0.41) and daily functioning (d-=0.43). Cognitive behavior therapy (CBT) was evaluated in the largest number of trials (21 trials), followed by hypnosis (4 trials), psychodynamic (3 trials), and relaxation (2 trials). The psychotherapeutic modalities were comparable with respect to their effect on mental health. CBT produced the greatest improvements to daily functioning, and this effect was significantly larger than that produced by relaxation therapy. These results have important clinical implications for treatment of adults with IBS.

Improving Outcome of Psychosocial Treatments by Enhancing Memory and Learning.

Mental disorders are prevalent and can lead to significant impairment. Some progress has been made toward establishing treatments; however, effect sizes are small to moderate, gains may not persist, and many patients derive no benefit. Our goal is to highlight the potential for empirically supported psychosocial treatments to be improved by incorporating insights from cognitive psychology and research on education. Our central question is: If it were possible to improve memory for the content of sessions of psychosocial treatments, would outcome substantially improve? We leverage insights from scientific knowledge on learning and memory to derive strategies for transdiagnostic and transtreatment cognitive support interventions. These strategies can be applied within and between sessions and to interventions delivered via computer, the Internet, and text message. Additional novel pathways to improving memory include improving sleep, engaging in exercise, and using imagery. Given that memory processes change across the lifespan, services to children and older adults may benefit from different types and amounts of cognitive support.

Cost and outcome of behavioural activation versus cognitive behaviour therapy for depression (COBRA): study protocol for a randomised controlled trial.

BACKGROUND: Cognitive behaviour therapy (CBT) is an effective treatment for depression. However, CBT is a complex therapy that requires highly trained and qualified practitioners, and its scalability is therefore limited by the costs of training and employing sufficient therapists to meet demand. Behavioural activation (BA) is a psychological treatment for depression that may be an effective alternative to CBT and, because it is simpler, might also be delivered by less highly trained and specialised mental health workers. METHODS/DESIGN: COBRA is a two-arm, non-inferiority, patient-level randomised controlled trial, including clinical, economic, and process evaluations comparing CBT delivered by highly trained professional therapists to BA delivered by junior professional or para-professional mental health workers to establish whether the clinical effectiveness of BA is non-inferior to CBT and if BA is cost effective compared to CBT. Four hundred and forty patients with major depressive disorder will be recruited through screening in primary care. We will analyse for non-inferiority in per-protocol and intention-to-treat populations. Our primary outcome will be severity of depression symptoms (Patient Health Questionnaire-9) at 12 months follow-up. Secondary outcomes will be clinically significant change and severity of depression at 18 months, and anxiety (General Anxiety Disorder-7 questionnaire) and health-related quality of life (Short-Form Health Survey-36) at 12 and 18 months. Our economic evaluation will take the United Kingdom National Health Service/Personal Social Services perspective to include costs of the interventions, health and social care services used, plus productivity losses. Cost-effectiveness will explored in terms of quality-adjusted life years using the EuroQol-5D measure of health-related quality of life. DISCUSSION: The clinical and economic outcomes of this trial will provide the evidence to help policy makers, clinicians and guideline developers decide on the merits of including BA as a first-line treatment of depression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27473954.

An update on the efficacy of psychological therapies in the treatment of obsessive-compulsive disorder in adults.

We conducted a review to provide an update on the efficacy of psychological treatments for OCD in general and with regard to specific symptom presentations. The PubMed and PsycINFO databases were searched for randomized controlled trials (RCTs) published up to mid February 2012. Forty-five such studies were identified. Exposure and response prevention (ERP) and cognitive-behavioral therapy (CBT) were found to be efficacious and specific for OCD. More purely cognitive interventions that did not include ERP or behavioral experiments were found to be possibly efficacious, as were Acceptance and Commitment Therapy, Motivational Interviewing as an adjunct to the established treatments, Eye Movement Desensitization and Reprocessing, and Satiation Therapy. There was little support for Stress Management or Psychodynamic Therapy. Although the majority of the studies recruited mixed or unspecified samples of patients and did not test for moderation, CBT was efficacious for obsessional patients who lacked overt rituals. One more purely cognitive intervention named Danger Ideation Reduction Therapy was found to be possibly efficacious for patients with contamination obsessions and washing compulsions. Although ERP and CBT are the best established psychological treatments for OCD, further research is needed to help elucidate which treatments are most effective for different OCD presentations.

Disrupting the rhythm of depression: design and protocol of a randomized controlled trial on preventing relapse using brief cognitive therapy with or without antidepressants.

BACKGROUND: Maintenance treatment with antidepressants is the leading strategy to prevent relapse and recurrence in patients with recurrent major depressive disorder (MDD) who have responded to acute treatment with antidepressants (AD). However, in clinical practice most patients (up to 70-80%) are not willing to take this medication after remission or take too low dosages. Moreover, as patients need to take medication for several years, it may not be the most cost-effective strategy. The best established effective and available alternative is brief cognitive therapy (CT). However, it is unclear whether brief CT while tapering antidepressants (AD) is an effective alternative for long term use of AD in recurrent depression. In addition, it is unclear whether the combination of AD to brief CT is beneficial. METHODS/DESIGN: Therefore, we will compare the effectiveness and cost-effectiveness of brief CT while tapering AD to maintenance AD and the combination of CT with maintenance AD. In addition, we examine whether the prophylactic effect of CT was due to CT tackling illness related risk factors for recurrence such as residual symptoms or to its efficacy to modify presumed vulnerability factors of recurrence (e.g. rigid explicit and/or implicit dysfunctional attitudes). This is a multicenter RCT comparing the above treatment scenarios. Remitted patients on AD with at least two previous depressive episodes in the past five years (n = 276) will be recruited. The primary outcome is time related proportion of depression relapse/recurrence during minimal 15 months using DSM-IV-R criteria as assessed by the Structural Clinical Interview for Depression. Secondary outcome: economic evaluation (using a societal perspective) and number, duration and severity of relapses/recurrences. DISCUSSION: This will be the first trial to investigate whether CT is effective in preventing relapse to depression in recurrent depression while tapering antidepressant treatment compared to antidepressant treatment alone and the combination of both. In addition, we explore explicit and implicit mediators of CT. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1907.

A review of empirically supported psychological therapies for mood disorders in adults.

BACKGROUND: The mood disorders are prevalent and problematic. We review randomized controlled psychotherapy trials to find those that are empirically supported with respect to acute symptom reduction and the prevention of subsequent relapse and recurrence. METHODS: We searched the PsycINFO and PubMed databases and the reference sections of chapters and journal articles to identify appropriate articles. RESULTS: One hundred twenty-five studies were found evaluating treatment efficacy for the various mood disorders. With respect to the treatment of major depressive disorder (MDD), interpersonal psychotherapy (IPT), cognitive behavior therapy (CBT), and behavior therapy (BT) are efficacious and specific and brief dynamic therapy (BDT) and emotion-focused therapy (EFT) are possibly efficacious. CBT is efficacious and specific, mindfulness-based cognitive therapy (MBCT) efficacious, and BDT and EFT possibly efficacious in the prevention of relapse/recurrence following treatment termination and IPT and CBT are each possibly efficacious in the prevention of relapse/recurrence if continued or maintained. IPT is possibly efficacious in the treatment of dysthymic disorder. With respect to bipolar disorder (BD), CBT and family-focused therapy (FFT) are efficacious and interpersonal social rhythm therapy (IPSRT) possibly efficacious as adjuncts to medication in the treatment of depression. Psychoeducation (PE) is efficacious in the prevention of mania/hypomania (and possibly depression) and FFT is efficacious and IPSRT and CBT possibly efficacious in preventing bipolar episodes. CONCLUSIONS: The newer psychological interventions are as efficacious as and more enduring than medications in the treatment of MDD and may enhance the efficacy of medications in the treatment of BD.

Empirically supported psychological treatments for adult acute stress disorder and posttraumatic stress disorder: a review.

BACKGROUND: Acute stress disorder (ASD) predicts the development of posttraumatic stress disorder (PTSD), which in some sufferers can persist for years and lead to significant disability. We carried out a review of randomized controlled trials to give an update on which psychological treatments are empirically supported for these disorders, and used the criteria set out by Chambless and Hollon [1998: J Consult Clin Psychol 66:7-18] to draw conclusions about efficacy, first irrespective of trauma type and second with regard to particular populations. METHODS: The PsycINFO and PubMed databases were searched electronically to identify suitable articles published up to the end of 2008. Fifty-seven studies satisfied our inclusion criteria. RESULTS: Looking at the literature undifferentiated by trauma type, there was evidence that trauma-focused cognitive behavioral therapy (CBT) and eye movement desensitization and reprocessing (EMDR) are efficacious and specific for PTSD, stress inoculation training, hypnotherapy, interpersonal psychotherapy, and psychodynamic therapy are possibly efficacious for PTSD and trauma-focused CBT is possibly efficacious for ASD. Not one of these treatments has been tested with the full range of trauma groups, though there is evidence that trauma-focused CBT is established in efficacy for assault- and road traffic accident-related PTSD. CONCLUSIONS: Trauma-focused CBT and to a lesser extent EMDR (due to fewer studies having been conducted and many having had a mixed trauma sample) are the psychological treatments of choice for PTSD, but further research of these and other therapies with different populations is needed.