Novel and emerging treatments for major depression.

Depression is common, costly, debilitating, and associated with increased risk of suicide. It is one of the leading global public health problems. Although existing available pharmacological treatments can be effective, their onset of action can take up to 6 weeks, side-effects are common, and recovery can require treatment with multiple different agents. Although psychosocial interventions might also be recommended, more effective treatments than those currently available are needed for people with moderate or severe depression. In the past 10 years, treatment trials have developed and tested many new targeted interventions. In this Review, we assess novel and emerging biological treatments for major depressive disorder, evaluate their putative brain and body mechanisms, and highlight how close each might be to clinical use.

Integrated rapid-cycle comparative effectiveness trials using flexible point of care randomisation in electronic health record systems.

Whilst the Randomised Controlled Trial remains the gold standard for deriving robust causal estimates of treatment efficacy, too often a traditional design proves prohibitively expensive or cumbersome when it comes to assessing questions regarding the comparative effectiveness of routinely used treatments. As a result, patients experience variation in practice as clinicians lack the evidence needed to personalise treatments effectively. This variation may be classified as unwarranted, where existing evidence is ignored, or legitimate where in the absence of evidence, clinicians rely on experience, expert opinion, and inferred principles from basic science to make decisions. We argue that within the right ethical and technological framework, legitimate variation can be transformed into a mechanism for evidence generation and learning. Learning Health Systems which harness existing variation in practice, represent a novel approach for generating evidence from everyday clinical practice. The development of these systems has gained traction due to the increased availability of modern Electronic Health Record Systems. However, despite their promise, overcoming hurdles to successfully integrating clinical trials within Learning Health Systems has proven challenging. This article describes the origins of integrated clinical trials and explores two main barriers to their further implementation - how best to obtain informed consent from patients to participate in routine comparative effectiveness research, and how to automate and integrate randomisation into a clinical workflow. Having described these barriers, we present a potential solution in the form of a research pipeline using a novel form of flexible point-of-care randomisation to allow clinicians and patients to participate in studies where there is clinical equipoise.

Descriptors of Sepsis Using the Sepsis-3 Criteria: A Cohort Study in Critical Care Units Within the U.K. National Institute for Health Research Critical Care Health Informatics Collaborative.

OBJECTIVES: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records. DESIGN: Retrospective cohort study using electronic health records. SETTING: Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative. PATIENTS: A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical). MEASUREMENTS AND MAIN RESULTS: Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9-25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5-19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1-13.6%) (p for comparison less than 0.0001). CONCLUSIONS: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding.

Personal digital health hubs for multiple conditions.

Multimorbidity is the presence of more than one chronic disease condition in an individual. Health-related, socioeconomic, cultural and environmental factors, as well as patient behaviour, all influence the outcomes of multimorbidity. Addressing these complex and often interacting biopsychosocial factors therefore requires a shift in treatment from a physical damage model towards person-centred integrated care with increased patient agency. Education influences behaviour and can be used to empower patients and their carers with greater agency, thus allowing greater responsibility for and control over the management of patient care. In this paper we reflect on our own learning as a community of health practitioners from different disciplines. Recognizing the increasing importance of patient agency in driving the evolution of health care, we describe the concept of a web-based personal digital health hub for integrated patient care. Informed by collaboration between patient, health and education communities, we share our early experience in the implementation of a health hub around a cohort of patients with hip fractures. We also describe a vision for future health care based on the co-creation of digital health hubs centred on patients' and carers' needs. The health hub could allow important advances and efficiencies to be achieved in workforce practice and education; patient and carer engagement in self-care; and the collection of patient-reported health data required for ongoing research and improvements in health care.

La multimorbidité est la présence de plus d'une maladie chronique chez un individu. L'aboutissement de la multimorbidité est influencé par des facteurs sanitaires, socio-économiques, culturels et environnementaux. Aborder ces facteurs biopsychosociaux complexes et souvent interdépendants requiert donc un changement de traitement, qui consiste à s'éloigner d'un modèle axé sur les dommages physiques pour se rapprocher d'un modèle de soins intégré et centré sur la personne, allié à une meilleure implication du patient. L'éducation a un impact sur le comportement et peut être utilisée pour renforcer la capacité d'agir des patients et de leurs soignants, ce qui permettra de conférer plus de responsabilités et un meilleur contrôle de la gestion des soins aux patients. Dans ce document, nous réfléchissons à notre propre apprentissage en tant que communauté de professionnels de la santé issus de différentes disciplines. Nous reconnaissons l'importance croissante de l'implication du patient pour stimuler l'évolution des soins de santé, et imaginons un concept de centre de santé numérique et personnalisé via site Web pour la prise en charge intégrée des patients. Grâce à la collaboration entre patients, professionnels de la santé et structures pédagogiques, nous partageons nos premières expériences en matière de mise en œuvre d'un centre de santé regroupant des patients présentant des fractures de la hanche. Nous dévoilons également notre vision d'avenir pour les soins de santé, qui repose sur la cocréation de centres de santé numériques adaptés aussi bien aux besoins des patients qu'à ceux des soignants. Ce concept pourrait faire progresser l'enseignement et la pratique pour les professionnels du secteur, mais aussi améliorer leur efficacité; favoriser la participation des patients et soignants dans les soins auto-administrés; et enfin, permettre la collecte des données fournies par les patients, et nécessaires à la poursuite des recherches et améliorations dans le domaine des soins de santé.

La multimorbilidad es la presencia de más de una enfermedad crónica en un individuo. Los factores medioambientales, culturales, socioeconómicos y los relacionados con la salud, así como el comportamiento de los pacientes, influyen en los resultados de la multimorbilidad. Por lo tanto, se requiere un cambio en el tratamiento desde el modelo de daño físico hacia una atención integrada y centrada en el individuo con una mayor participación del paciente para abordar estos factores biopsicosociales complejos y a menudo interactivos. La educación influye en el comportamiento y se puede utilizar para que los pacientes y sus cuidadores tengan más capacidad de acción, lo que permite una mayor responsabilidad y control sobre la gestión de la atención al paciente. En este documento reflexionamos sobre nuestro propio aprendizaje como comunidad de profesionales de la salud de diferentes disciplinas. Se describe el concepto de un centro de salud virtual personalizado para la atención integrada del paciente, al reconocer la creciente relevancia de la participación y la acción del paciente en el proceso de evolución de la atención médica. Gracias a la colaboración entre las comunidades de pacientes, de salud y de educación, compartimos nuestra experiencia inicial sobre el establecimiento de un centro de salud en torno a una cohorte de pacientes con fracturas de cadera. Asimismo, describimos una visión de la futura atención médica basada en la creación conjunta de centros de salud virtuales que se centran en las necesidades de los pacientes y de los cuidadores. El centro de salud permitiría alcanzar importantes avances y mejoras en la práctica y la educación de la fuerza de trabajo; en el compromiso de los pacientes y los cuidadores con el autocuidado de la salud; y en la recopilación de los datos sobre la salud que los pacientes comunican y que se requieren para la investigación y las mejoras continuas en la atención médica.

The Association between Supraphysiologic Arterial Oxygen Levels and Mortality in Critically Ill Patients. A Multicenter Observational Cohort Study.

Rationale: There is conflicting evidence on harm related to exposure to supraphysiologic PaO2 (hyperoxemia) in critically ill patients.Objectives: To examine the association between longitudinal exposure to hyperoxemia and mortality in patients admitted to ICUs in five United Kingdom university hospitals.Methods: A retrospective cohort of ICU admissions between January 31, 2014, and December 31, 2018, from the National Institute of Health Research Critical Care Health Informatics Collaborative was studied. Multivariable logistic regression modeled death in ICU by exposure to hyperoxemia.Measurements and Main Results: Subsets with oxygen exposure windows of 0 to 1, 0 to 3, 0 to 5, and 0 to 7 days were evaluated, capturing 19,515, 10,525, 6,360, and 4,296 patients, respectively. Hyperoxemia dose was defined as the area between the PaO2 time curve and a boundary of 13.3 kPa (100 mm Hg) divided by the hours of potential exposure (24, 72, 120, or 168 h). An association was found between exposure to hyperoxemia and ICU mortality for exposure windows of 0 to 1 days (odds ratio [OR], 1.15; 95% compatibility interval [CI], 0.95-1.38; P = 0.15), 0 to 3 days (OR 1.35; 95% CI, 1.04-1.74; P = 0.02), 0 to 5 days (OR, 1.5; 95% CI, 1.07-2.13; P = 0.02), and 0 to 7 days (OR, 1.74; 95% CI, 1.11-2.72; P = 0.02). However, a dose-response relationship was not observed. There was no evidence to support a differential effect between hyperoxemia and either a respiratory diagnosis or mechanical ventilation.Conclusions: An association between hyperoxemia and mortality was observed in our large, unselected multicenter cohort. The absence of a dose-response relationship weakens causal interpretation. Further experimental research is warranted to elucidate this important question.

Evaluation of the utility of teaching joint relocations using cadaveric specimens.

BACKGROUND: Like other procedural skills, the ability to relocate a joint is an important aspect of junior doctor education. Changes in the approach to teaching and learning from the traditional apprenticeship-style model have made the teaching of practical skills more difficult logistically. Workshops utilising cadaveric specimens offer a solution to this problem. METHODS: One hundred forty-six fourth year medical students were randomly divided into 5 groups. Each group received a different teaching intervention based on ankle, patella and hip relocation. The interventions consisted of online learning modules, instructional cards and workshops using skeleton models and cadaveric dislocation models. Following the intervention students were given a test containing multiple choice and true/false style questions. A 13-item 5-point Likert scale questionnaire was also delivered before and after the intervention. The data was analysed using one-way analysis of variance (ANOVA) and the Bonferroni post-hoc test. RESULTS: Compared to the instructional cards group, the other 4 groups showed a 10.8-19.2% improvement in total test score (p < 0.01) and an 18.4-25.3% improvement in self-reported understanding and confidence in performing joint relocations (P < 0.01). There was no significant difference in total test scores between groups exposed to cadaveric instruction on the relocation of one-, two- or all three- joints, nor any significant difference between all the cadaveric dislocation groups and the group receiving instruction on the skeleton model. CONCLUSION: The results of the present study suggest that workshops utilising cadaveric dislocation models are effective in teaching joint relocation. In addition, the finding that lower fidelity models may be of equal utility may provide institutions with flexibility of delivery needed to meet financial and resource constraints.

Optic Nerve Head Drusen: An Update.

Optic nerve head drusen are benign acellular calcium concretions that usually form early in life, just anterior to the lamina cribrosa. Improving imaging using optical coherence tomography suggests they are common and may be present in many clinically normal discs. These drusen may change in appearance in early life, but are generally stable in adulthood, and may be associated with visual field defects, anterior ischaemic optic neuropathy, or rarer complications. Based on long-term clinical data and optical coherence tomography, we propose a refined hypothesis as to the cause of optic disc drusen. Here we summarise recent findings and suggest future studies to better understand the forces involved.

Are there gender differences in wellbeing related to work status among persons with severe impairments?

AIM: The aim of this study was to analyse gender differences in wellbeing, as related to work status, among working-age people with severe impairments. METHODS: This study is based on register and survey data for a sample of 7298 persons, drawn from the entire Swedish population of 15,515 working-age people 16-64 years old who, at the end of 2010, received Sweden's unique personal assistance allowance, an allowance paid from the Swedish Social Insurance Agency (SSIA) to persons with severe impairments, enabling them to pay for assistants to support them in the functions of daily life. Logistic regression models were used to estimate the strength of relations between six measures of wellbeing, work status (not working, irregular work and regular work) and gender, together with key confounders. RESULTS: Of the persons surveyed, 21% responded that they had regular work. Gender differences were found for all confounders, except for age. They were mostly in favour of men, which could reflect the general pattern in the labour market at large. Our results indicated there are substantial differences between non-working, irregularly working and working persons for several wellbeing aspects. CONCLUSIONS: This study analyses the contributions to wellbeing of work participation among working-age people with severe impairments, with a focus on gender differences. The analysis shows that work is an important determinant of the six measures of wellbeing examined, where the relationship between work participation and wellbeing is especially strong for peoples' perceived standard of living. This major finding holds for both genders; however, the data show gender imbalance, in that compared with women, there was a larger percentage of men with severe impairments who have regular work. Future research should focus on finer distinctions between the types of work and the value added of personal assistants in the work context. Measures of general health not available for this study are needed to filter out a clearer picture of the interaction of work and well-being. Despite drawbacks, this study is nevertheless path-breaking in its focus on the value of work participation for the well-being of persons with severe impairments. For this reason, it provides a valuable extension of our knowledge and a clear point of departure for future studies.

Sickness absence and subsequent disposable income: A population-based cohort study.

AIMS: Studies show a negative association between an absence from work due to disease of injury (sickness absence (SA)) and subsequent earnings; however, little is known about the association between SA and an individuals' subsequent overall economic welfare. Our primary objective was to evaluate individuals' disposable income (DI) following a spell of SA. Our secondary objective was to examine if the potential association between SA and DI differs, depending on the diagnosis given to that sickness or the duration of the SA spell. METHODS: We used a cohort based on a linked individual register database that includes all individuals living in Sweden from 2001 to 2005, aged 30-54. DI was measured 2-6 years after a spell of SA and compared with a propensity score-matched reference group (individuals without SA in 2005). Each year of follow-up during 2007-2011 was estimated by linear regression for three different forms of exposure: SA (yes/no), diagnosis specific (cancer, circulatory, injuries, musculoskeletal or mental illnesses), and by duration of the SA spell (15-29, 30-89, 90-179 or > 179 days). RESULTS: Individuals with SA during 2005 had 4% lower disposable income in subsequent years than the reference group. Our results were similar across diagnoses, except for mental diagnoses, where disposable income was 7-10% lower than the reference group; and for cancer, where we found only a marginal difference among those with SA and the reference group. Furthermore, DI was negatively associated with the SA spell duration. CONCLUSIONS: SA was associated with lower subsequent DI, 2­6 years after a SA spell, especially after a mental illness diagnosis and if the SA was for longer spells.

The assessment of a structured online formative assessment program: a randomised controlled trial.

BACKGROUND: Online formative assessment continues to be an important area of research and methods which actively engage the learner and provide useful learning outcomes are of particular interest. This study reports on the outcomes of a two year study of medical students using formative assessment tools. METHOD: The study was conducted over two consecutive years using two different strategies for engaging students. The Year 1 strategy involved voluntary use of the formative assessment tool by 129 students. In Year 2, a second cohort of 130 students was encouraged to complete the formative assessment by incorporating summative assessment elements into it. Outcomes from pre and post testing students around the formative assessment intervention were used as measures of learning. To compare improvement scores between the two years a two-way Analysis of Variance (ANOVA) model was fitted to the data. RESULTS: The ANOVA model showed that there was a significant difference in improvement scores between students in the two years (mean improvement percentage 19% vs. 38.5%, p < 0.0001). Students were more likely to complete formative assessment items if they had a summative component. In Year 2, the time spent using the formative assessment tool had no impact on student improvement, nor did the number of assessment items completed. CONCLUSION: The online medium is a valuable learning resource, capable of providing timely formative feedback and stimulating student-centered learning. However the production of quality content is a time-consuming task and careful consideration must be given to the strategies employed to ensure its efficacy. Course designers should consider the potential positive impact summative components to formative assessment may have on student engagement and outcomes.

Trajectories of Inflammation in Youth and Risk of Mental and Cardiometabolic Disorders in Adulthood.

Importance: Research suggests that low-grade, nonresolving inflammation may predate adult mental and physical illness. However, evidence to date is largely cross-sectional or focuses on single disorder outcomes. Objectives: To examine trajectories of inflammation as measured by C-reactive protein (CRP) levels in a large sample of children and adolescents, and to explore associations between different identified trajectories and mental and related cardiometabolic health outcomes in early adulthood. Design, Setting, and Participants: In a longitudinal cohort study using data from the large UK-based Avon Longitudinal Study of Parents and Children (ALSPAC), latent class growth analysis (LCGA) was used to explore different trajectories of inflammation, with logistic regression exploring association with mental and physical health outcomes. Participants with measurable CRP data and associated mental and cardiometabolic health outcomes recorded were included in the analysis. Data analysis was performed from May 1, 2023, to March 30, 2024. Exposures: Inflammation was assessed via CRP levels at ages 9, 15, and 17 years. LCGA was used to identify different trajectories of inflammation. Main Outcomes and Measures: Outcomes assessed at age 24 years included psychotic disorders, depressive disorders, anxiety disorders, hypomania, and, as a measure of insulin resistance, Homeostasis Model Assessment (HOMA2) score. Results: A total of 6556 participants (3303 [50.4%] female) were included. Three classes of inflammation were identified: persistently low CRP levels (reference class, n = 6109); persistently raised CRP levels, peaking at age 9 years (early peak, n = 197); and persistently raised CRP levels, peaking at age 17 years (late peak, n = 250). Participants in the early peak group were associated with a higher risk of psychotic disorder (odds ratio [OR], 4.60; 95% CI, 1.81-11.70; P = .008), a higher risk of severe depression (OR, 4.37; 95% CI, 1.64-11.63; P = .02), and higher HOMA2 scores (ß = 0.05; 95% CI, 0.01-0.62, P = .04) compared with participants with persistently low CRP. The late peak group was not associated with any outcomes at age 24 years. Conclusions and Relevance: Low-grade systemic inflammation peaking in midchildhood was associated with specific mental and cardiometabolic disorders in young adulthood. These findings suggest that low-grade persistent inflammation in early life may be an important shared common factor for mental-physical comorbidity and so could be relevant to future efforts of patient stratification and risk profiling.

Subtle variation in sepsis-III definitions markedly influences predictive performance within and across methods.

Early detection of sepsis is key to ensure timely clinical intervention. Since very few end-to-end pipelines are publicly available, fair comparisons between methodologies are difficult if not impossible. Progress is further limited by discrepancies in the reconstruction of sepsis onset time. This retrospective cohort study highlights the variation in performance of predictive models under three subtly different interpretations of sepsis onset from the sepsis-III definition and compares this against inter-model differences. The models are chosen to cover tree-based, deep learning, and survival analysis methods. Using the MIMIC-III database, between 867 and 2178 intensive care unit admissions with sepsis were identified, depending on the onset definition. We show that model performance can be more sensitive to differences in the definition of sepsis onset than to the model itself. Given a fixed sepsis definition, the best performing method had a gain of 1-5% in the area under the receiver operating characteristic (AUROC). However, the choice of onset time can cause a greater effect, with variation of 0-6% in AUROC. We illustrate that misleading conclusions can be drawn if models are compared without consideration of the sepsis definition used which emphasizes the need for a standardized definition for sepsis onset.

Altruism or self-interest in tomorrow's veterinarians? A metric conjoint experiment and cluster analysis.

Introduction: Altruism is considered a trait of veterinary and other health professionals, but the level of altruism in the veterinary profession is unknown. We designed a metric conjoint experiment to reveal other-orientation (an individual's caring concern for the wellbeing of others) and self-interest. We draw on the 'Theory of Other-Orientation', which states that individuals' decision-making heuristics can be impacted by their other-orientation independent of their self-interest. In patient-focused contexts, highly other-oriented or altruistic (veterinary) professionals may care too much for others and suffer immediate or cumulative financial and personal costs of such caring. At the same time, other-orientation can enhance job-related attitudes and outcomes, such as job satisfaction. Methods: In a metric conjoint experiment, Australian final-year veterinary, science, nursing, entrepreneurship, and engineering students rated eight job scenarios with orthogonally arranged high and low levels of three job characteristics (n = 586) to provide observed measures of other-orientation and self-interest. Results: A two-way MANOVA showed other-orientation or self-interest differed per discipline, but not gender. Veterinary (and engineering) respondents were less other-oriented than nursing respondents. Veterinary (and entrepreneurship) respondents were more self-interested than nursing respondents. K-Means cluster analysis confirmed four distinct profile groupings-altruistic/self-sacrificing, 'both other-self', self-interested and selfish-aligning with the discourse in the literature. Human nursing respondents stood out for the most members (50%) in the 'both other-self' profile compared to veterinary respondents (28%). Respondents of one of three veterinary schools stood out for the most members (19%) in the altruistic/self-sacrificing group. Discussion: Our metric conjoint experiment illustrates an alternative to 'self-report' items with Likert-scaled responses. Our finding of the 'both other-self' group adds to the literature, which considers that other-orientation and self-interest are separate constructs that are difficult to co-exist in individuals. This mix of traits is deemed helpful by organizational psychology scholars, for sustainability and wellbeing, especially for healthcare professionals involved in high-frequency and intense, patient-focused interactions. Our findings highlight the need for more research on the potential role of other-orientation and self-interest in veterinary school admissions processes, the hidden or taught curricula, job-related attitudes and beliefs, and wellbeing and professional sustainability in the veterinary sector.

Business Intentions of Australian Veterinary Students-My Business or Yours? A Cluster Analysis.

Little is known about veterinary entrepreneurial predisposition. Yet entrepreneurship and intrapreneurship (entrepreneurial behaviour of employees) foster business innovation and growth and support wealth creation and employment in both privately and corporately owned businesses which deliver contemporary veterinary services. We used responses from 515 final-year students in Australian entrepreneurship, nursing, and veterinary programs to capture entrepreneurial intention (EI), outcome expectations (OE-sb), entrepreneurial self-efficacy (ESE), and corporate/large organisation work intentions (CWIs). Veterinary respondents stood out for their high EI and high OE-sb, but low financial ESE and low CWI. Proportions of veterinary, entrepreneurship, and nursing respondents differed markedly across distinct cluster profiles representing entrepreneurial, intrapreneurial, both entrepreneurial and intrapreneurial, indifferent, and corporate employment intentions and attributes. Post hoc analysis revealed proportional cluster membership differences for respondents from different veterinary schools. Our findings raise questions regarding (1) the effectiveness of veterinary business curricula competencies which focus on expense management and (2) the implications of the mismatch of motivations and goals of new veterinary sector entrants whose low intent to work in a corporate environment is at odds with increasing corporate ownership of veterinary practices. To inform curricular change, we recommend further research to evaluate the relative impact of individual factors, admissions factors, and the formal or hidden curricula on entrepreneurial intention in veterinary final-year students.

Antidepressants for the prevention of depression following first-episode psychosis (ADEPP): study protocol for a multi-centre, double-blind, randomised controlled trial.

BACKGROUND: Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. METHODS: The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. DISCUSSION: The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. TRIAL REGISTRATION: ISRCTN12682719 registration date 24/11/2020.

Persistent Childhood and Adolescent Anxiety and Risk for Psychosis: A Longitudinal Birth Cohort Study.

BACKGROUND: Persistent anxiety in childhood and adolescence could represent a novel treatment target for psychosis, potentially targeting activation of stress pathways and secondary nonresolving inflammatory response. Here, we examined the association between persistent anxiety through childhood and adolescence with individuals with psychotic experiences (PEs) or who met criteria for psychotic disorder (PD) at age 24 years. We also investigated whether C-reactive protein mediated any association. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were available in 8242 children at age 8 years, 7658 at age 10 years, 6906 at age 13 years, and 3889 at age 24 years. The Development and Well-Being Assessment was administered to capture child and adolescent anxiety. We created a composite score of generalized anxiety at ages 8, 10, and 13. PEs and PD were assessed at age 24, derived from the Psychosis-like Symptoms Interview. The mean of C-reactive protein at ages 9 and 15 years was used as a mediator. RESULTS: Individuals with persistent high levels of anxiety were more likely to develop PEs (odds ratio 2.02, 95% CI 1.26-3.23, p = .003) and PD at age 24 (odds ratio 4.23, 95% CI 2.27-7.88, p < .001). The mean of C-reactive protein at ages 9 and 15 mediated the associations of persistent anxiety with PEs (bias-corrected estimate -0.001, p = .013) and PD (bias-corrected estimate 0.001, p = .003). CONCLUSIONS: Persistent high levels of anxiety through childhood and adolescence could be a risk factor for psychosis. Persistent anxiety is potentially related to subsequent psychosis via activation of stress hormones and nonresolving inflammation. These results contribute to the potential for preventive interventions in psychosis, with the novel target of early anxiety.