Determinants of patient-reported outcome trajectories and symptomatic recovery in Improving Access to Psychological Therapies (IAPT) services.

BACKGROUND: Despite evidence for the general effectiveness of psychological therapies, there exists substantial heterogeneity in patient outcomes. We aimed to identify factors associated with baseline severity of depression and anxiety symptoms, rate of symptomatic change over the course of therapy, and symptomatic recovery in a primary mental health care setting. METHODS: Using data from a service evaluation involving 35 527 patients in England's psychological and wellbeing [Improving Access to Psychological Therapies (IAPT)] services, we applied latent growth models to explore which routinely-collected sociodemographic, clinical, and therapeutic variables were associated with baseline symptom severity and rate of symptomatic change. We used a multilevel logit model to determine variables associated with symptomatic recovery. RESULTS: Being female, younger, more functionally impaired, and more socioeconomically disadvantaged was associated with higher baseline severity of both depression and anxiety symptoms. Being older, less functionally impaired, and having more severe baseline symptomatology was associated with more rapid improvement of both depression and anxiety symptoms (male gender and greater socioeconomic disadvantage were further associated with rate of change for depression only). Therapy intensity and appointment frequency seemed to have no correlation with rate of symptomatic improvement. Patients with lower baseline symptom severity, less functional impairment, and older age had a greater likelihood of achieving symptomatic recovery (as defined by IAPT criteria). CONCLUSIONS: We must continue to investigate how best to tailor psychotherapeutic interventions to fit patients' needs. Patients who begin therapy with more severe depression and/or anxiety symptoms and poorer functioning merit special attention, as these characteristics may negatively impact recovery.

Critical preparation and readiness to support future change.

The challenging nature of change is well documented and adequate preparation before implementing a change initiative is critical to reducing resistance and increasing its chances of success. This article describes a service review conducted in preparation for possible change and improvement at an internationally ranked school of nursing and midwifery in an Irish tertiary education institution. The purpose of the review was to examine organisational structures and work activities, including pressures facing the administrative team that supports the school, and to establish whether operations were fit for purpose and capable of continuing to support the international ranking. The article outlines the importance of change to maintain a competitive edge and the critical role of leadership during change. The background and rationale for the service review are discussed along with the methods used to prepare staff. The article also reports outcomes of the surveys and focus groups undertaken and discusses the main recommendations and changes implemented so far. It also suggests how the outcomes are relevant to clinical practice.

A collaborative realist review of remote measurement technologies for depression in young people.

Digital mental health is becoming increasingly common. This includes use of smartphones and wearables to collect data in real time during day-to-day life (remote measurement technologies, RMT). Such data could capture changes relevant to depression for use in objective screening, symptom management and relapse prevention. This approach may be particularly accessible to young people of today as the smartphone generation. However, there is limited research on how such a complex intervention would work in the real world. We conducted a collaborative realist review of RMT for depression in young people. Here we describe how, why, for whom and in what contexts RMT appear to work or not work for depression in young people and make recommendations for future research and practice. Ethical, data protection and methodological issues need to be resolved and standardized; without this, RMT may be currently best used for self-monitoring and feedback to the healthcare professional where possible, to increase emotional self-awareness, enhance the therapeutic relationship and monitor the effectiveness of other interventions.

A Realist Evaluation of Social Care Practitioners' Experiences With and Understanding of Applied Healthcare Research.

Social care practitioners are often under-represented in research activity and output. Evidence-based practice enables social care practitioners to develop/engage the skills to evaluate evidence and be more actively involved in research. REalist Synthesis Of non-pharmacologicaL interVEntions for antipsychotic-induced weight gain (RESOLVE) is a NIHR-funded study where realist synthesis is used to understand and explain how, why, for whom, and in what contexts non-pharmacological interventions help service users, with severe mental illness, to manage antipsychotic-induced weight gain. Social care practitioners are a key part of the team providing care for people living with severe mental illness and therefore supporting antipsychotic-induced weight gain. The current study, RESOLVE 2, uses realist evaluation and RESOLVE as an illustrative example to help understand why and how social care practitioners engage (or not) with research. Semi-structured, audio-recorded interviews will be undertaken with a purposive sample of approximately 20 social care practitioners working with people who have severe mental illness, are treated with antipsychotics, and have experienced weight gain. Participants will be recruited from NHS Trusts and recruitment avenues such as social media and personal networks. Topics discussed during interviews will include barriers and facilitators to engagement in research, current, and past engagement as well as recommendations for researchers and other practitioners. Interview recordings will be transcribed verbatim and analyzed using realist evaluation which will allow in-depth causal explanations for research engagement. Better understanding of research engagement by social care practitioners will allow for evidence-based practice and better patient outcomes within these settings.

Heart rate variability (HRV) as a way to understand associations between the autonomic nervous system (ANS) and affective states: A critical review of the literature.

Evidence suggests affective disorders such as depression and bipolar disorder are characterised by dysregulated autonomic nervous system (ANS) activity. These findings suggest ANS dysregulation may be involved in the pathogenesis of affective disorders. Different affective states are characterised by different ANS activity patterns (i.e., an increase or decrease in sympathetic or parasympathetic activity). To understand how ANS abnormalities are involved in the development of affective disorders, it is important to understand how affective states correlate with ANS activity before their onset. Using heart rate variability (HRV) as a tool to measure ANS activity, this review aimed to look at associations between affective states and HRV in non-clinical populations (i.e., in those without medical and psychiatric disorders). Searches on PubMed and Google Scholar were completed using the following search terms: heart rate variability, autonomic nervous system, sympathetic nervous system, parasympathetic nervous system, affective state, mood and emotion in all possible combinations. All but one of the studies examined (N = 13), demonstrated significant associations between affect and HRV. Findings suggest negative affect, encompassing both diffused longer-term experiences (i.e., mood) as well as more focused short-term experiences (i.e., emotions), may be associated with a reduction in parasympathetic activity as measured through HRV parameters known to quantify parasympathetic activity (e.g., high frequency (HF)-HRV). HRV measures typically linked to reduction in parasympathetic activity appear to be linked to negative affective states in non-clinical populations. However, given the complex and possibly non-linear relationship between HRV and parasympathetic activity, further studies need to clarify specificity of these findings. Future studies should investigate the potential utility of HRV measures as biomarkers for monitoring changes in affective states and for early detection of onset and relapse of depression in patients with affective disorders.

Psychological and contextual risk factors for first-onset depression among adolescents and young people around the globe: A systematic review and meta-analysis.

AIM: Identifying predictors for future onset of depression is crucial to effectively developing preventive interventions. We conducted a systematic review and meta-analysis to identify risk factors for first-onset depression among adolescents and young people. METHODS: We searched MEDLINE (Ovid), PsycINFO, Cochrane Database, Web of Science, Lilacs, African Journals Online and Global Health (July 2009 to December 2020) for longitudinal studies assessing risk factors for first-onset depression among adolescents and young people aged 10-25 years. Meta-analyses generated summary odds ratio (OR) estimates. REGISTRATION: PROSPERO CRD42018103973. RESULTS: Nineteen studies representing 21 unique populations were included in the meta-analysis. Among studies reporting race/ethnicity, 79% of participants were of White/European descent. Seventeen studies were from high-income countries, with only two from an upper-middle-income country (China). Odds for first-onset depression were significantly greater for girls compared to boys (n = 13; OR = 1.78 [1.78, 2.28], p < 0.001) and for youth with other mental health problems at baseline (n = 4; OR = 3.20 [1.95, 5.23], p < 0.001). There were non-significant associations for negative family environment (n = 8; OR = 1.60 [0.82, 3.10], p = 0.16) and parental depression (n = 3; OR = 2.30 [0.73, 7.24], p = 0.16). CONCLUSIONS: Most longitudinal studies do not report risk factors specifically for first-onset depression. Moreover, predictive data are limited to predominantly White populations in high-income countries. Future research must be more ethnically and geographically representative. Recommendations are provided for consistent and comprehensive reporting of study designs and analyses of risk factors for first-onset depression.

Biochemical and Cellular Characterization of the Function of Fluorophosphonate-Binding Hydrolase H (FphH) in Staphylococcus aureus Support a Role in Bacterial Stress Response.

The development of new treatment options for bacterial infections requires access to new targets for antibiotics and antivirulence strategies. Chemoproteomic approaches are powerful tools for profiling and identifying novel druggable target candidates, but their functions often remain uncharacterized. Previously, we used activity-based protein profiling in the opportunistic pathogen Staphylococcus aureus to identify active serine hydrolases termed fluorophosphonate-binding hydrolases (Fph). Here, we provide the first characterization of S. aureus FphH, a conserved, putative carboxylesterase (referred to as yvaK in Bacillus subtilis) at the molecular and cellular level. First, phenotypic characterization of fphH-deficient transposon mutants revealed phenotypes during growth under nutrient deprivation, biofilm formation, and intracellular survival. Biochemical and structural investigations revealed that FphH acts as an esterase and lipase based on a fold well suited to act on a small to long hydrophobic unbranched lipid group within its substrate and can be inhibited by active site-targeting oxadiazoles. Prompted by a previous observation that fphH expression was upregulated in response to fusidic acid, we found that FphH can deacetylate this ribosome-targeting antibiotic, but the lack of FphH function did not infer major changes in antibiotic susceptibility. In conclusion, our results indicate a functional role of this hydrolase in S. aureus stress responses, and hypothetical functions connecting FphH with components of the ribosome rescue system that are conserved in the same gene cluster across Bacillales are discussed. Our atomic characterization of FphH will facilitate the development of specific FphH inhibitors and probes to elucidate its physiological role and validity as a drug target.

Sex-specific inflammatory markers of risk and presence of depression in adolescents.

BACKGROUND: Associations between inflammatory markers and depression are reported among adults; however, less is known in adolescent depression in particular whether these associations are sex-specific. We aimed to identify inflammatory markers of increased risk and presence of depression in adolescence and their association with severity of depressive symptoms in the entire cohort and separately in boys and girls. METHODS: We measured serum cytokines using a Meso Scale Discovery electrochemiluminescence V-PLEX assay in a cohort of 150 adolescents stratified for risk/presence of depression. Risk group and sex-specific differences in inflammatory markers were assessed with 2-way mixed ANOVA, and sex-moderated associations between inflammatory markers and the severity of depressive symptoms were assessed with moderated multiple hierarchical regression analyses. RESULTS: We found a significant interaction between biological sex and the risk group, where boys showed higher interleukin (IL)-2 levels among the depressed group compared with the low-risk group. The severity of depressive symptoms was associated with elevated levels of IL-2 in boys, and of IL-6 in girls. There was a significant moderating effect of sex on the relationship between IL-2 and the severity of depressive symptoms but not for IL-6. LIMITATIONS: The cross-sectional design means that we cannot be certain about the direction of the associations. CONCLUSIONS: Our findings suggest sex-specific associations between inflammatory markers and the development of adolescent depression, where IL-2 may increase risk for depression and severity of depressive symptoms in boys, but not in girls. However, IL-6 may increase risk for more severe depressive symptoms in girls.

Cortisol and development of depression in adolescence and young adulthood - a systematic review and meta-analysis.

INTRODUCTION: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of major depressive disorder (MDD) in adulthood. Less work has focused on the role of the HPA axis in depression in adolescence and young adulthood globally. The aim of this study was to conduct a systematic review and meta-analysis of worldwide research investigating the relationship between cortisol, a measure of HPA axis activity, and MDD in adolescence and young adulthood. METHOD: We searched MEDLINE, PsycINFO, Cochrane Database of Systematic Reviews, Web of Science, Lilacs, African Journals Online, and Global Health for studies which examined the relationship between cortisol and MDD in global youth (10-24 years old). RESULTS: Twenty-six studies were included in the systematic review and 14 were eligible for the meta-analysis, but only one study included young adults in their sample. Results from the meta-analysis demonstrated that elevated morning, but not evening, cortisol levels was prospectively associated with later MDD development in adolescence and young adulthood. However, morning cortisol levels did not significantly differ between healthy controls and individuals with MDD in cross-sectional studies. Afternoon cortisol and cortisol stress response also did not differ between adolescents with MDD and healthy controls. Qualitative synthesis of the three studies examining nocturnal cortisol showed higher nocturnal cortisol was both longitudinally and cross-sectionally associated with MDD in adolescence. CONCLUSION: Our findings suggest elevated morning cortisol precedes depression in adolescence. Despite this, we did not find any differences in other cortisol measures in association with MDD in cross-sectional studies. Taken together, these findings suggest that elevated morning and nocturnal cortisol are risk factors for depression in adolescence rather than a biomarker of existing MDD. This supports a role for the hyperactivity of the HPA axis in the development of MDD in adolescence. Most of the studies were from high-income-countries (HICs) and thus further work would need to be conducted in low- and middle-income countries (LMICs) to understand if our findings are generalisable also to these populations.

A systematic review of the association between biological markers and environmental stress risk factors for adolescent depression.

INTRODUCTION: Although the aetiology and pathophysiology of depression are multifactorial, to date most studies have examined either biological or environmental mechanisms without looking at the integration of both; with most studies conducted in high-income countries (HICs). Therefore, we conducted a systematic review of worldwide studies investigating the relationship between biological and environmental stress risk factors for major depressive disorder (MDD) in adolescence. METHODS: We searched MEDLINE (via Ovid), PsycINFO, Cochrane Database of Systematic Reviews, Web of Science (Core Collection), Lilacs, African Journals Online and Global Health for prospective and cross-sectional studies that examined the association between biological markers and environmental stress risk factors in MDD during adolescence. FINDINGS: Of 11,089 articles identified, 21 were included, with only two from middle-income countries. Increased inflammation, telomere length and brain abnormalities, including blunted reward-related activity, white matter disruptions, and altered volume of limbic brain regions, were associated with increased risk for MDD mainly in the context of early life adversity. There is little evidence suggesting that the neurobiological changes investigated were associated with MDD in the context of recent life stress. INTERPRETATION: The developmental trajectory of depression appears to start with early life adversities and occurs in the context of immune and brain abnormalities. Understanding these biopsychosocial processes will help to improve our ability to detect individuals at risk of developing depression in adolescence. However, generalizability is limited by few studies examining both biological and environmental stress risk factors and a lack of studies on adolescents and young adults in low-and-middle-income countries (LMICs).

Exploring the role of immune pathways in the risk and development of depression in adolescence: Research protocol of the IDEA-FLAME study.

Extensive research suggests a role for the innate immune system in the pathogenesis of depression, but most of the studies are conducted in adult populations, in high-income countries and mainly focus on the study of inflammatory proteins alone, which provides only a limited understanding of the immune pathways involved in the development of depression. The IDEA-FLAME study aims to identify immune phenotypes underlying increased risk of developing depression in adolescence in a middle-income country. To this end, we will perform deep-immunophenotyping of peripheral blood mononuclear cells and RNA genome-wide gene expression analyses in a longitudinal cohort of Brazilian adolescents stratified for depression risk. The project will involve the 3-year follow-up of an already recruited cohort of 150 Brazilian adolescents selected for risk/presence of depression on the basis of a composite risk score we developed using sociodemographic characteristics (50 adolescents with low-risk and 50 with high-risk of developing depression, and 50 adolescents with a current major depressive disorder). We will 1) test whether the risk group classification at baseline is associated with differences in immune cell frequency, phenotype and functional status, 2) test whether baseline immune markers (cytokines and immune cell markers) are associated with severity of depression at 3-year follow-up, and 3) identify changes in gene expression of immune pathways over the 3-year follow-up in adolescents with increased risk and presence of depression. Because of the exploratory nature of the study, the findings would need to be replicated in a separate and larger sample. Ultimately, this research will contribute to elucidating key immune therapeutic targets and inform the development of interventions to prevent onset of depression among adolescents.

The Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo): Rationale, Methods, and Baseline Characteristics.

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS). Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers. Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample. Results: A total of 7,720 adolescents aged 14-16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group. Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence.

A Dissociation of the Acute Effects of Bupropion on Positive Emotional Processing and Reward Processing in Healthy Volunteers.

Background: Previous research indicates that antidepressants can restore the balance between negative and positive emotional processing early in treatment, indicating a role of this effect in later mood improvement. However, less is known about the effect of antidepressants on reward processing despite the potential relevance to the treatment of anhedonia. In this study, we investigated the effects of an acute dose of the atypical antidepressant (dual dopamine and noradrenaline reuptake inhibitor) bupropion on behavioral measures of emotional and reward processing in healthy volunteers. Methods: Forty healthy participants were randomly allocated to double-blind intervention with either an acute dose of bupropion or placebo prior to performing the Emotional Test Battery (ETB) and a probabilistic instrumental learning task. Results: Acute bupropion significantly increased the recognition of ambiguous faces as happy, decreased response bias toward sad faces and reduced attentional vigilance for fearful faces compared to placebo. Bupropion also reduced negative bias compared to placebo in the emotional recognition memory task (EMEM). There was no evidence that bupropion enhanced reward processing or learning. Instead, bupropion was associated with reduced likelihood to choose high-probability wins and increased score on a subjective measure of anhedonia. Conclusions: Whilst acute bupropion decreases negative and increases positive emotional processing, it has an adverse effect on reward processing. There seems to be a dissociation of the acute effects of bupropion on positive emotional processing and reward processing, which may have clinical implications for anhedonia early in treatment.

Dissociable temporal effects of bupropion on behavioural measures of emotional and reward processing in depression.

Antidepressants remediate negative biases in emotional processing early in treatment, prior to mood improvement. However, the effects on reward processing potentially relevant to the treatment of anhedonia are less clear. Here we investigate the early and sustained effects of the dopamine and noradrenaline reuptake inhibitor bupropion on behavioural measures of emotional and reward processing in currently depressed individuals. Forty-six currently depressed patients and 42 healthy controls participated in a repeated measures study, during which open-label bupropion was administered to only the patient group over a six week period without a placebo group. All participants completed the Emotional Test Battery and a probabilistic instrumental learning task at week 0, week 2 and week 6. Currently depressed patients displayed negative biases in emotional processing and blunted response bias for high-probability wins compared to the healthy controls at baseline. Bupropion was found to reduce the negative biases in emotional processing early in treatment, including a significant decrease in the percentage misclassification of other face emotions as sad and the number of negative self-referent words falsely recalled between baseline and week 2. Conversely, bupropion was found to initially further reduce the response bias for high-probability wins between baseline and week 2. This effect reversed with six weeks' bupropion treatment and reward processing was normalized compared to the healthy controls. Early in treatment, bupropion acts to reduce negative biases in emotional processing but exacerbates impaired reward processing. The beneficial actions of bupropion on reward processing then occur later in treatment. Such dissociation in the temporal effects of bupropion on emotional and reward processing has implications for the treatment of the different symptom domains of negative affect and anhedonia in depression.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

No evidence for an acute placebo effect on emotional processing in healthy volunteers.

Placebo-controlled trials are the gold standard measure of efficacy in the development of new treatments for depression. However, the large placebo effects associated with standard measures of subjective symptoms reduce the sensitivity of such trials to detect antidepressant effects. There is a need to develop novel efficacy markers that are resistant to placebo effects. Measures of emotional processing, known to be sensitive to antidepressant treatment, may be such a marker, although the effect of an acute placebo treatment on these measures remains unclear. We assessed the influence of placebo on a validated battery of emotional processing tasks, the Emotional Test Battery (ETB), in healthy participants. Participants were informed they might receive the antidepressant drug bupropion, placebo or no treatment, with placebo effect being estimated as the difference between the placebo and no treatment groups. We found no significant difference between these groups on measures of emotional processing. There was also no effect of subjective treatment expectancy on performance in the tasks. This suggests that the ETB might be a useful tool for Phase I trials assessing novel antidepressant agents against placebo.

Does Faux Pas Detection in Adult Autism Reflect Differences in Social Cognition or Decision-Making Abilities?

43 typically-developed adults and 35 adults with ASD performed a cartoon faux pas test. Adults with ASD apparently over-detected faux pas despite good comprehension abilities, and were generally slower at responding. Signal detection analysis demonstrated that the ASD participants had significantly greater difficulty detecting whether a cartoon depicted a faux pas and showed a liberal response bias. Test item analysis demonstrated that the ASD group were not in agreement with a reference control group (n = 69) about which non-faux pas items were most difficult. These results suggest that the participants with ASD had a primary problem with faux pas detection, but that there is another factor at work, possibly compensatory, that relates to their choice of a liberal response criterion.