The complexity of treatment-resistant depression: A data-driven approach.

BACKGROUND: Recent systematic reviews highlight great variability in defining and assessing treatment-resistant depression (TRD). A key problem is that definitions are consensus rather than data-led. This study seeks to offer a comprehensive socio-demographic and clinical description of a relevant sample. METHODS: As part of a pragmatic randomized controlled trial, patients (N = 129) were managed in primary care for persistent depression and diagnosed with TRD. Data included previous treatment attempts, characteristics of the depressive illness, functioning, quality of life, co-occurring problems including suicidality, psychiatric and personality disorders, physical health conditions, and adverse events. RESULTS: Findings show a severe and chronic course of depression with a duration of illness of 25+ years. Overall, 82.9 % had at least one other psychiatric diagnosis and 82.2 % at least one personality disorder; 69.8 % had significant musculoskeletal, gastrointestinal, genitourinary, or cardiovascular and respiratory physical health problems. All but 14 had severe difficulties in social and occupational functioning and reported severely impaired quality of life. Suicidal ideation was high: 44.9 % had made at least one serious suicide attempt and several reported multiple attempts with 17.8 % reporting a suicide attempt during childhood or adolescence. Of the patients, 79.8 % reported at least one adverse childhood experience. LIMITATIONS: Potential for recall bias, not examining possible interactions, and absence of a control group. CONCLUSIONS: Our findings reveal a complex and multifaceted condition and call for an urgent reconceptualization of TRD, which encompasses many interdependent variables and experiences. Individuals with TRD may be at a serious disadvantage in terms of receiving adequate treatment.

Cost-effectiveness of long-term psychoanalytic psychotherapy for treatment-resistant depression: RCT evidence from the Tavistock Adult Depression Study (TADS).

BACKGROUND: Treatment-resistant depression (TRD) accounts for a large fraction of the burden of depression. The interventions currently used are mostly pharmacological and short-term psychotherapies, but their effectiveness is limited. The Tavistock Adult Depression Study found evidence for the effectiveness of long-term psychoanalytic psychotherapy (LTPP) plus treatment as usual (TAU), versus TAU alone, for TRD. Even after a 2-year follow-up, moderate effect sizes were sustained. This study assessed the cost-effectiveness of this LTPP + TAU. METHODS: We conducted a within-trial economic evaluation using a Bayesian framework. RESULTS: Quality-adjusted life years (QALYs) were 0.16 higher in the LTPP + TAU group compared with TAU. The direct cost of LTPP was £5500, with no substantial compensating savings elsewhere. Overall, average health and social care costs in the LTPP + TAU group were £5000 more than in the TAU group, employment rates were unchanged, and effects on other non-healthcare costs were uncertain. Accordingly, the incremental cost-effectiveness ratio was ≈£33,000/QALY; the probability that LTPP + TAU was cost-effective at a willingness to pay of £20,000/QALY was 18 %. LIMITATIONS: The sample size of this study was relatively small, and the fraction of missing service-use data was approximately 50 % at all time points. The study was conducted at a single site, potentially reducing generalizability. CONCLUSIONS: Although LTPP + TAU was found to be clinically effective for treating TRD, it was not found to be cost-effective compared with TAU. However, given the sustained effects over the follow-up period it is likely that the time horizon of this study was too short to capture all benefits of LTPP augmentation.

Kailo: a systemic approach to addressing the social determinants of young people's mental health and wellbeing at the local level.

The mental health and wellbeing of children and young people is deteriorating. It is increasingly recognised that mental health is a systemic issue, with a wide range of contributing and interacting factors. However, the vast majority of attention and resources are focused on the identification and treatment of mental health disorders, with relatively scant attention on the social determinants of mental health and wellbeing and investment in preventative approaches. Furthermore, there is little attention on how the social determinants manifest or may be influenced at the local level, impeding the design of contextually nuanced preventative approaches. This paper describes a major research and design initiative called Kailo that aims to support the design and implementation of local and contextually nuanced preventative strategies to improve children's and young people's mental health and wellbeing. The Kailo Framework involves structured engagement with a wide range of local partners and stakeholders - including young people, community partners, practitioners and local system leaders - to better understand local systemic influences and support programmes of youth-centred and evidence-informed co-design, prototyping and testing. It is hypothesised that integrating different sources of knowledge, experience, insight and evidence will result in better embedded, more sustainable and more impactful strategies that address the social determinants of young people's mental health and wellbeing at the local level.

Development and validation of a self-report measure of epistemic trust.

Epistemic trust (ET) refers to trust in communicated knowledge. This paper describes the development and validation of a new self-report questionnaire, the Epistemic Trust, Mistrust and Credulity Questionnaire (ETMCQ). We report on two studies (Study 1, n = 500; Study 2, n = 705) examining the psychometric properties of the ETMCQ and the relationship between EMTCQ scores (i.e., an individual's epistemic stance) and exposure to adverse childhood experiences, mental health symptoms, attachment, mentalizing and general self-efficacy. The factor structure of the ETMCQ was examined using Exploratory and Confirmatory Factor Analyses, and its reliability and test-retest reliability were tested. Both studies yielded three correlated yet distinct factors-Trust, Mistrust and Credulity-and confirmed the reliability and validity of the ETMCQ. Preregistered hypotheses were confirmed and replicated across both studies. Main findings suggest intriguing links between the ETMCQ and developmental psychopathology constructs and are consistent with thinking on the role of epistemic stance in undermining adaptation and increasing the developmental risk of mental health problems. Mistrust and Credulity scores were associated with childhood adversity and higher scores on the global psychopathology severity index and both factors partially mediated the link between early adversity and mental health symptoms. Mistrust and Credulity were positively associated with difficulties in understanding mental states and insecure attachment styles. Post-hoc analysis identified that different attachment styles were associated with differences in epistemic stance. In addition, Trust was not associated with reduced levels of mental health symptoms and did not moderate the impact of childhood adversity-findings are congruent with the suggestion that the reduction of mistrust and credulity may be crucial common factors in promoting resilience and the effectiveness of psychotherapeutic interventions. This investigation and the ETMCQ provide an empirical measure of what until now has been largely a theoretical concept and open new avenues for future research.

Interlaminar versus transforaminal epidural steroid injections for the treatment of symptomatic lumbar spinal stenosis.

BACKGROUND: Lumbar spinal stenosis is a common condition that causes axial low back pain, radicular pain, and neurogenic claudication. Epidural steroid injections are commonly used for the treatment of radicular symptoms and neurogenic claudication associated with symptomatic lumbar spinal stenosis. No prior study has evaluated whether transforaminal or interlaminar epidural steroid injections produce better clinical outcomes. DESIGN: Retrospective case control study. METHODS: For each technique, 19 patients were retrospectively identified who received their first fluoroscopically guided epidural steroid injection for radicular and neurogenic claudication symptoms caused by lumbar spinal stenosis over a 12-month interval. All patients had corresponding MRI findings and had failed previous non-invasive therapies. Outcomes included the visual analog scale (VAS, 0-10 scale) immediately before the injection, immediately after the injection, and upon follow up at 4-6 weeks. Surgery rates and number of repeat injections over a 3 year period were also analyzed. The patient groups were matched for age and level of stenosis on MRI. RESULTS: There was no statistically significant difference between the two groups in pre injection to follow up VAS scores (P=0.919). The difference between number of repeat injections between the interlaminar and transforaminal groups was not statistically significant (0.91-mean 2.47 and 2.58, respectively). Both the interlaminar and transforaminal groups experienced statistically significant improvement in VAS scores from before the injection to after the injection, and on follow up. Low numbers underwent surgery (11% in the interlaminar group vs 15% in the transforaminal group, not significant, P=0.63). CONCLUSIONS: In the current study, neither transforaminal nor interlaminar steroid injections resulted in superior short term pain improvement or fewer long term surgical interventions or repeat injections when compared with each other.

The homeoprotein engrailed 1 has pleiotropic functions in calvarial intramembranous bone formation and remodeling.

The membranous bones of the mammalian skull vault arise from discrete condensations of neural crest- and mesodermally-derived cells. Recently, a number of homeodomain transcription factors have been identified as critical regulators of this process. Here, we show that the homeoprotein engrailed 1 (EN1) is expressed during embryonic and perinatal craniofacial bone development, where it localizes to the skeletogenic mesenchyme, and, subsequently, to calvarial osteoblasts and osteoprogenitors. Mice lacking En1 exhibit generalized calvarial bone hypoplasia and persistent widening of the sutural joints. A reduction in calvarial membranous bone deposition and mineralization (osteopenia) is coupled to enhanced osteolytic resorption in En1 mutants. Consistent with these observations, expression of established osteoblast differentiation markers reveals that En1 function is required for both early and late phases of calvarial osteogenesis. Further analysis shows that EN1 regulates FGF signaling in calvarial osteoblasts. Moreover, EN1 indirectly influences calvarial osteoclast recruitment and bone resorption by regulating the expression of receptor activator of NFkappaB ligand (RANKL) in osteoblasts. Thus, during intramembranous bone formation, EN1 acts both cell autonomously and non-cell autonomously. In summary, this study identifies EN1 as a novel modulator of calvarial osteoblast differentiation and proliferation, processes that must be exquisitely balanced to ensure proper skull vault formation.