Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation.

INTRODUCTION: Observational studies indicate a potentially causal role for interleukin 6 (IL-6), a proinflammatory cytokine, in pathogenesis of depression, but interventional studies based on patients with depression have not been conducted. Tocilizumab, anti-inflammatory drug, is a humanised monoclonal antibody that inhibits IL-6 signalling and is licensed in the UK for treatment of rheumatoid arthritis. The main objectives of this study are to test whether IL-6 contributes to the pathogenesis of depression and to examine potential mechanisms by which IL-6 affects mood and cognition. A secondary objective is to compare depressed participants with and without evidence of low-grade systemic inflammation. METHODS AND ANALYSIS: This is a proof-of-concept, randomised, parallel-group, double-blind, placebo-controlled clinical trial. Approximately 50 participants with International Classification of Diseases 10th revision (ICD-10) diagnosis of depression who have evidence of low-grade inflammation, defined as serum high-sensitivity C reactive protein (hs-CRP) level ≥3 mg/L, will receive either a single intravenous infusion of tocilizumab or normal saline. Blood samples, behavioural and cognitive measures will be collected at baseline and after infusion around day 7, 14 and 28. The primary outcome is somatic symptoms score around day 14 postinfusion. In addition, approximately, 50 depressed participants without low-grade inflammation (serum hs-CRP level <3 mg/L) will complete the same baseline assessments as the randomised cohort. ETHICS AND DISSEMINATION: The study has been approved by the South Central-Oxford B Research Ethics Committee (REC) (Reference: 18/SC/0118). Study findings will be published in peer-review journals. Findings will be also disseminated by conference/departmental presentations and by social and traditional media. TRIAL REGISTRATION NUMBER: ISRCTN16942542; Pre-results

How is a specialist depression service effective for persistent moderate to severe depressive disorder?: a qualitative study of service user experience

Background. A specialist depression service (SDS) offering collaborative pharmacological and cognitive behaviour therapy treatment for persistent depressive disorder showed effectiveness against depression symptoms versus usual community based multidisciplinary care in a randomised controlled trial (RCT) in specialist mental health services in England. However, there is uncertainty concerning how specialist depression services effect such change. The current study aimed to evaluate the factors which may explain the greater effectiveness of SDS compared to Treatment as Usual (TAU) by exploring the experience of the RCT participants .Methods. Qualitative audiotaped and transcribed semi-structured interviews were conducted 12-18 months after baseline with 21 service users (12 SDS, 9 TAU arms) drawn from all three sites. Inductive thematic analysis using a grounded approach contrasted the experiences of SDS with TAU participants.Results. Four themes emerged in relation to service user experience: 1. Specific treatment components of the SDS: which included sub-themes of the management of medication change, explaining and developing treatment strategies, setting realistic expectations, and person-centred and holistic approach; 2. Individual qualities of SDS clinicians; 3. Collaborative team context in SDS: which included sub-themes of communication between healthcare professionals, and continuity of team members; 4. Accessibility to SDS: which included sub-themes of flexibility of locations, frequent consultation as reinforcement, gradual pace of treatment, and challenges of returning to usual care.Conclusions. The study uncovered important mechanisms and contextual factors in the SDS that service users experience as different from TAU, and which may explain the greater effectiveness of the SDS: the technical expertise of the healthcare professionals, personal qualities of clinicians, teamwork, gradual pace of care, accessibility and managing service transitions. Usual care in other specialist mental health services may share many of the features from the SDS.Trial Registration: “Trial of the Clinical and Cost Effectiveness of a Specialist Expert Mood Disorder Team for Refractory Unipolar Depressive Disorder” was registered in www.ClinicalTrials.gov (NCT01047124) on 12-01-2010 and the ISRCTN registry (ISRCTN10963342) on 25-11-2015 (retrospectively registered)

Emotional complexity across the life story: Diminished positive emodiversity and elevated negative emodiversity in sufferers of chronic depression

Greater diversity in the experience of negative and positive emotion – emodiversity - is associated with better mental health outcomes in the general population (Quoidbach et al. 2014). However, conceptual accounts of clinical depression suggest that extensive and prolonged exposure to negative emotional states might actually be reflected in enhanced diversity across negative emotion experiences. Conversely, the opportunity to experience a myriad of varied positive emotions is likely to be reduced in depression, given existing deficits in positive affective experience associated with the disorder. In this study, the diversity of negative and positive emotion experiences in a treatment-resistant chronically depressed sample and a never-depressed control group were compared. We hypothesized that depressed individuals (n=22) would show enhanced emodiversity in the negative emotion domain but reduced emodiversity in the positive domain, relative to the control group (n=20). Results supported these hypotheses. Analyses also showed that among those with depression, reduced positive emodiversity was associated with disorder chronicity, such that both length of time depressed and frequency of past episodes were linked to reduced positive emodiversity. No support was found for an association between negative emotion diversity and depression chronicity. This study provides the first investigation into the relationship between clinical depression and emodiversity, and suggests that supporting depressed individuals to experience a range of diverse positive emotions could be a valuable therapeutic target

Emotional complexity across the life story: Diminished positive emodiversity and elevated negative emodiversity in sufferers of chronic depression

Greater diversity in the experience of negative and positive emotion – emodiversity - is associated with better mental health outcomes in the general population (Quoidbach et al. 2014). However, conceptual accounts of clinical depression suggest that extensive and prolonged exposure to negative emotional states might actually be reflected in enhanced diversity across negative emotion experiences. Conversely, the opportunity to experience a myriad of varied positive emotions is likely to be reduced in depression, given existing deficits in positive affective experience associated with the disorder. In this study, the diversity of negative and positive emotion experiences in a treatment-resistant chronically depressed sample and a never-depressed control group were compared. We hypothesized that depressed individuals (n=22) would show enhanced emodiversity in the negative emotion domain but reduced emodiversity in the positive domain, relative to the control group (n=20). Results supported these hypotheses. Analyses also showed that among those with depression, reduced positive emodiversity was associated with disorder chronicity, such that both length of time depressed and frequency of past episodes were linked to reduced positive emodiversity. No support was found for an association between negative emotion diversity and depression chronicity. This study provides the first investigation into the relationship between clinical depression and emodiversity, and suggests that supporting depressed individuals to experience a range of diverse positive emotions could be a valuable therapeutic target

Emotional complexity across the life story: Elevated negative emodiversity and diminished positive emodiversity in sufferers of recurrent depression.

BACKGROUND: Greater diversity in the experience of negative and positive emotions - emodiversity - is associated with better mental health outcomes in the general population (Quoidbach et al. 2014). However, conceptual accounts of depression suggest this might differ in clinical depression. In this study, the diversity of negative and positive emotion experiences as remembered by a recurrently depressed sample and a never-depressed control group were compared. METHODS: Emodiversity was assessed using a life structure card sort task which allowed for the assessment of memory for emotional experience over the life course. Depressed (n=34) and non-depressed (n=34) participants completed the card sort task, from which emodiversity metrics were calculated for negative and positive emotion experience. RESULTS: Depressed individuals showed recollections of enhanced emodiversity across negative emotion but reduced emodiversity across positive emotion, relative to never-depressed individuals. LIMITATIONS: This study involved a relatively small sample size. DISCUSSION: This study indicates that greater diversity of negative emotion experience, which has been interpreted as a protective factor against depressed mood in community samples (Quoidbach et al., 2014), instead characterises the remembered experience of recurrent clinical depression. The finding that positive emodiversity is adaptive in depression suggests that therapeutic outcomes may be improved by facilitating exposure to a diverse range of positive emotions. These findings indicate that the relationship between emotion diversity and mental health is more complex than hitherto assumed.This work was funded by the UK Medical Research Council(GrantReference: SUAG/043 G101400) and supported by the National Institute for Health Research Cambridge Biomedica lResearch Centre

Factor structure and longitudinal measurement invariance of PHQ-9 for specialist mental health care patients with persistent major depressive disorder: Exploratory Structural Equation Modelling.

BACKGROUND: The Patient Health Questionnaire-9 (PHQ-9) is a widely used instrument for measuring levels of depression in patients in clinical practice and academic research; its factor structure has been investigated in various samples, with limited evidence of measurement equivalence/invariance (ME/I) but not in patients with more severe depression of long duration. This study aims to explore the factor structure of the PHQ-9 and the ME/I between treatment groups over time for these patients. METHODS: 187 secondary care patients with persistent major depressive disorder (PMDD) were recruited to a randomised controlled trial (RCT) with allocation to either a specialist depression team arm or a general mental health arm; their PHQ-9 score was measured at baseline, 3, 6, 9 and 12 months. Exploratory Structural Equational Modelling (ESEM) was performed to examine the factor structure for this specific patient group. ME/I between treatment arm at and across follow-up time were further explored by means of multiple-group ESEM approach using the best-fitted factor structure. RESULTS: A two-factor structure was evidenced (somatic and affective factor). This two-factor structure had strong factorial invariance between the treatment groups at and across follow up times. LIMITATIONS: Participants were largely white British in a RCT with 40% attrition potentially limiting the study's generalisability. Not all two-factor modelling criteria were met at every time-point. CONCLUSION: PHQ-9 has a two-factor structure for PMDD patients, with strong measurement invariance between treatment groups at and across follow-up time, demonstrating its validity for RCTs and prospective longitudinal studies in chronic moderate to severe depression

Mplus ESEM code testing factor structure and longitudinal measurement invariance of PHQ-9 for specialist mental health care patients with persistent major depressive disorder

The files are Mplus code used to perform ESEM models presented in paper "Factor structure and longitudinal measurement invariance of PHQ-9 for specialist mental health care patients with persistent major depressive disorder: Exploratory Structural Equation Modelling", submitted to Journal of Affective Disorders (2017)