Publications by authors named "A J Young"

6,198 Publications

SITAgliptin for Depressive Symptoms (SITADS) in type 2 diabetes: a feasibility randomized controlled trial.

Psychosom Med 2021 Jul 21. Epub 2021 Jul 21.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RJ, UK Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL and SE5 9RJ, UK Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.

Objective: We tested the feasibility of using sitagliptin - a dipeptidyl peptidase-IV inhibitor - for depressive symptoms in type 2 diabetes (T2D).

Methods: In a feasibility, double-blind, randomised controlled trial, we recruited people aged 18-75 with T2D (HbA1c ≥53 and ≤ 86 mmol/mol prescribed oral hypoglycaemic therapy) and comorbid depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥ 10) from family practices in South London. Eligible patients were randomised to sitagliptin 100 mg per day or matched placebo for 12 weeks. The primary feasibility outcomes were participation rates, attrition rates and adverse events. The primary clinical outcomes were depressive symptoms (PHQ-9 and Quick Inventory of Depressive Symptomatology [QIDS-SR-16] scores) at 12 weeks as assessed using ANCOVA analyses. Ranges of treatment effects were estimated using Cohen's d and associated 95% confidence intervals, where negative values favoured sitagliptin over placebo.

Results: Of 153 people screened across 32 practices, 44 were randomised (22 to each arm). The mean age was 58.8 (SD = 8.3) years, 46% were female and 52% of non-white ethnicity. Of those treated, 1 patient (4.5%) in each arm withdrew and there were no group differences in adverse events. Despite improving 12-week HbA1c (d = -1.19 [95% CI -1.90, -0.48]), improvement in 12-week QIDS-SR-16 score with sitagliptin was inferior to placebo across the range of estimated treatment effects (d = 0.71 [0.13, 1.30]). Effects of sitagliptin on inflammation were inconsistent (d = -0.32 [-0.81, 0.17] for hs-CRP).

Conclusions: Repositioning of oral hypoglycaemic therapy for depressive symptoms in T2D is feasible. However, in this under-powered feasibility study, we did not detect evidence of superiority of sitagliptin over placebo. The results are cautioned by the small sample size and limited treatment duration.Trial RegistrationEudraCT: 2015-004527-32.
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http://dx.doi.org/10.1097/PSY.0000000000000985DOI Listing
July 2021

Bbc3 loss enhances survival and protein clearance in neurons exposed to the organophosphate pesticide chlorpyrifos.

Toxicol Sci 2021 Jul 21. Epub 2021 Jul 21.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH.

Exposure to environmental toxicants can increase the risk of developing age-related neurodegenerative disorders. Exposure to the widely used organophosphate pesticide chlorpyrifos (CPF) is associated with increased risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD), but the cellular mechanisms underlying CPF toxicity in neurons are not completely understood. We evaluated CPF toxicity in mouse primary cortical neuronal cultures, using RNA-Seq to identify cellular pathways modulated by CPF. CPF exposure altered the expression of genes associated with intrinsic apoptosis, significantly elevating expression of the pro-apoptotic mediator Bbc3/Puma. Bbc3 loss attenuated CPF driven neurotoxicity, induction of other intrinsic apoptosis regulatory genes including Trp53 and Pmaip1 (encoding the NOXA protein), and cleavage of apoptosis executors caspase 3 and PARP. CPF exposure was associated with enhanced expression of ER stress-related genes and proteins and the accumulation of high molecular weight protein species in primary neuronal cultures. No evidence of alterations in the ubiquitin-proteosome system were observed, however, autophagy-related proteins were upregulated in CPF-treated Bbc3-/- neuronal cultures compared with identically exposed WT cultures. Elevated autophagy-related protein expression in Bbc3-/- neuronal cultures was associated with a reduction in CPF-induced high molecular weight alpha-synuclein and tau immunoreactive protein aggregates. Studies indicate that Bbc3-/- neuronal cultures enhance the ER stress response and upregulate protein clearance mechanisms as a component of resistance to CPF-mediated toxicity.
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http://dx.doi.org/10.1093/toxsci/kfab090DOI Listing
July 2021

Iris Depigmentation in the Prediction of Cytomegalovirus Anterior Uveitis.

Ocul Immunol Inflamm 2021 Jul 20:1-6. Epub 2021 Jul 20.

Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.

Purpose: We hypothesize that the presence of iris depigmentation is associated with the prediction of cytomegalovirus (CMV) as the etiology of chronic or recurrent anterior uveitis.

Methods: A prospective cohort study on patients with recurrent or chronic anterior uveitis. Pre-operative data on iris depigmentation and corneal endothelial cell densities were compared between eyes with and without CMV.

Results: Forty-one eyes of 38 subjects with a mean age of 61.1 ± 11.2 years old were recruited. Seventeen eyes were positive for CMV. A greater proportion of eyes with CMV showed severe or diffuse iris depigmentation than eyes without CMV, and possessed larger corneal endothelial cells ( = .028). When severe iris depigmentation was present with a reduced endothelial cell density, the positive and negative predictive values were raised to 100.0% and 64.9% from 41.5% and 58.5%, respectively.

Conclusion: Iris depigmentation is a potential clinical biomarker in predicting CMV in chronic or recurrent anterior uveitis.
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http://dx.doi.org/10.1080/09273948.2021.1952277DOI Listing
July 2021

Cardiovascular Effects of Combining Subcutaneous or Intravenous Esketamine and the MAO Inhibitor Tranylcypromine for the Treatment of Depression: A Retrospective Cohort Study.

CNS Drugs 2021 Jul 20. Epub 2021 Jul 20.

Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Background: (Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous administration is currently not recommended because of concern about hypertensive crises.

Objective: Our objective was to evaluate whether changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during esketamine administration differed between patients who concomitantly received tranylcypromine and those who did not.

Methods: This was a retrospective cohort study utilizing cardiovascular monitoring data from inpatients treated for severe depression in unipolar, bipolar, and schizoaffective disorder. Primary outcomes were change in mean BP and HR during the first hour after intravenous or subcutaneous esketamine administration compared with baseline, controlled for confounders. Secondary analyses quantify differences in absolute BP during esketamine treatment and comparisons of BP peaks, temporal effects, and intraindividual comparisons before and after tranylcypromine initiation.

Results: Our analysis included 509 esketamine administrations in 43 patients, 14 of whom concomitantly received tranylcypromine. Controlling for creatinine and age, mean ± standard deviation (SD) BP changes were significantly increased by concomitant tranylcypromine treatment (ΔSBP: F[1,503] = 86.73, p < 0.001; ΔDBP: F[1,503] = 55.71, p < 0.001), but HR remained unaffected. Mean SBP change during esketamine administration was 2.96 ± 18.11 mmHg in patients receiving tranylcypromine (TCP+) and -8.84 ± 11.31 mmHg in those who did not (TCP-). Changes in DBP were -2.81 ± 11.20 mmHg for TCP+ and -10.77 ± 9.13 mmHg for TCP-. Moreover, we found a significant dose-response relationship between tranylcypromine dose and BP (SBP: B = 0.35, standard error [SE] = 0.12, 95% confidence interval [CI] 0.12-0.60, p = 0.004; adjusted R = 0.11, p = 0.008; DBP: B = 0.21, SE = 0.08, 95% CI 0.06-0.36, p = 0.007; adjusted R = 0.08; p = 0.023).

Conclusions: Although statistically significant changes in BP were identified in patients receiving tranylcypromine and esketamine, these changes were clinically insignificant. Thus, combining esketamine and this MAOI appears to be safe at standard doses. The dose-response relationship calls for caution with higher doses of tranylcypromine.
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http://dx.doi.org/10.1007/s40263-021-00837-6DOI Listing
July 2021

Topical Review: Medical Trauma During Early Childhood.

J Pediatr Psychol 2021 Jul 20. Epub 2021 Jul 20.

Department of Counseling and Clinical Psychology, Columbia University Teachers College.

Objective: Early childhood is a high-risk period for exposure to traumatic medical events due to injury/illness. It is also one of the most important and vulnerable periods due to rapid development in neurobiological systems, attachment relationships, cognitive and linguistic capacities, and emotion regulation. The aim of this topical review is to evaluate empirical literature on the psychological impact of medical trauma during early childhood (0-6 years) to inform models of clinical care for assessing, preventing, and treating traumatic stress following injury/illness.

Methods: Topical review of empirical and theoretical literature on pediatric medical traumatic stress (PMTS) during early childhood.

Results: There are important developmental factors that influence how infants and young children perceive and respond to medical events. The emerging literature indicates that up to 30% of young children experience PMTS within the first month of an acute illness/injury and between 3% and 10% develop posttraumatic stress disorder. However, significant knowledge gaps remain in our understanding of psychological outcomes for infants and young children, identification of risk-factors and availability of evidence-based interventions for medical trauma following illness.

Conclusions: This topical review on medical trauma during early childhood provides: (a) definitions of key medical trauma terminology, (b) discussion of important developmental considerations, (c) summary of the empirical literature on psychological outcomes, risk factors, and interventions, (d) introduction to a stepped-model-of-care framework to guide clinical practice, and (e) summary of limitations and directions for future research.
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http://dx.doi.org/10.1093/jpepsy/jsab045DOI Listing
July 2021