Publications by authors named "Allan H Young"

372 Publications

Cognitive impairment in euthymic patients with bipolar disorder: Prevalence estimation and model selection for predictors of cognitive performance.

J Affect Disord 2021 Jul 21;294:497-504. Epub 2021 Jul 21.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London & Maudsley NHS Foundation Trust, Maudsley Hospital, London, UK.

Objectives Although cognitive dysfunction is a prominent feature of bipolar disorder (BD), previous research presents limitations in estimating the proportion of euthymic patients experiencing clinically relevant deficits and identifying predictors of cognitive difficulties. We explored the relevance of recommended definitions of clinically significant cognitive impairment for functional outcomes, estimated its prevalence, and identified patient characteristics associated with cognition. Methods We assessed cognitive performance across four domains in 80 euthymic participants with BD. Participants were categorized based on two criteria for clinically significant cognitive impairment and we assessed the ability of these criteria to differentiate participant performance on established functional outcomes. Variable selection with elastic net regression was used to identify sociodemographic and clinical factors associated with cognitive performance. Selected variables were examined as predictors of clinically significant cognitive impairment with logistic regression. Results According to the selected criterion, 34% presented with clinically significant cognitive impairment. Poorer current cognitive performance was associated with older age, lower estimated premorbid IQ, more currently prescribed psychotropic medications, fewer previous psychological therapies, and current use of antipsychotics. A model with premorbid IQ, psychotropic medications and previous psychological therapies as predictors of cognitive impairment correctly classified 75% of the participants. Conclusions This is one of the first studies to use a model selection approach to identify factors associated with cognitive difficulties in BD. Our findings offer the initial steps towards a predictive model for cognitive impairment. This could improve treatment decisions and prioritization for euthymic patients with BD, particularly the implementation of cognitive interventions.
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http://dx.doi.org/10.1016/j.jad.2021.07.036DOI Listing
July 2021

The : La Plus ça change. . .

Authors:
Allan H Young

J Psychopharmacol 2021 Jul 28:2698811211036951. Epub 2021 Jul 28.

Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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http://dx.doi.org/10.1177/02698811211036951DOI Listing
July 2021

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

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

A Novel Group Cognitive Behavioral Therapy Approach to Adult Non-rapid Eye Movement Parasomnias.

Front Psychiatry 2021 1;12:679272. Epub 2021 Jul 1.

Sleep Disorder Centre, Nuffield House, Guy's Hospital, London, United Kingdom.

Following the success of Cognitive Behavioral Therapy (CBT) for insomnia, there has been a growing recognition that similar treatment approaches might be equally beneficial for other major sleep disorders, including non-rapid eye movement (NREM) parasomnias. We have developed a novel, group-based, CBT-program for NREM parasomnias (CBT-NREMP), with the primary aim of reducing NREM parasomnia severity with relatively few treatment sessions. We investigated the effectiveness of CBT-NREMP in 46 retrospectively-identified patients, who completed five outpatient therapy sessions. The outcomes pre- and post- CBT-NREMP treatment on clinical measures of insomnia (Insomnia Severity Index), NREM parasomnias (Paris Arousal Disorders Severity Scale) and anxiety and depression (Hospital Anxiety and Depression Scale), were retrospectively collected and analyzed. In order to investigate the temporal stability of CBT-NREMP, we also assessed a subgroup of 8 patients during the 3 to 6 months follow-up period. CBT-NREMP led to a reduction in clinical measures of NREM parasomnia, insomnia, and anxiety and depression severities [pre- vs. post-CBT-NREMP scores: (Insomnia Severity Index) = 0.000054; (Paris Arousal Disorders Severity Scale) = 0.00032; (Hospital Anxiety and Depression Scale) = 0.037]. Improvements in clinical measures of NREM parasomnia and insomnia severities were similarly recorded for a subgroup of eight patients at follow-up, demonstrating that patients continued to improve post CBT-NREMP. Our findings suggest that group CBT-NREMP intervention is a safe, effective and promising treatment for NREM parasomnia, especially when precipitating and perpetuating factors are behaviorally and psychologically driven. Future randomized controlled trials are now required to robustly confirm these findings.
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http://dx.doi.org/10.3389/fpsyt.2021.679272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281294PMC
July 2021

Morbidity and mortality associated with electroconvulsive therapy: can we control for confounding?

Lancet Psychiatry 2021 08 12;8(8):643-644. Epub 2021 Jul 12.

Centre for Affective Disorders, Psychological Medicine, IoPPN, King's College London, London, UK.

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http://dx.doi.org/10.1016/S2215-0366(21)00238-8DOI Listing
August 2021

'Melancholy can be overwhelmed only by melancholy.' Robert Burton, Anatomy of Melancholy.

Int Rev Psychiatry 2021 May;33(3):205-206

Centre for Affective Disorders, Psychological Medicine, IoPPN, King's College, London, UK.

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http://dx.doi.org/10.1080/09540261.2021.1936853DOI Listing
May 2021

Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study).

BMC Psychiatry 2021 07 5;21(1):334. Epub 2021 Jul 5.

Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle, UK.

Background: Treatment Resistant Bipolar Depression (TRBD) is a major contributor to the burden of disease associated with Bipolar Disorder (BD). Treatment options for people experiencing bipolar depression are limited to three interventions listed by National Institute for Health and Care: lamotrigine, quetiapine and olanzapine, of which the latter two are often not well tolerated. The majority of depressed people with BD are therefore prescribed antidepressants despite limited efficacy. This demonstrates an unmet need for additional interventions. Pramipexole has been shown to improve mood symptoms in animal models of depression, in people with Parkinson's Disease and two proof of principle trials of pramipexole for people with BD who are currently depressed.

Methods: The PAX-BD study, funded by the United Kingdom (UK) National Institute for Health Research, aims to extend previous findings by assessing the efficacy, safety and health economic impact of pramipexole in addition to mood stabilisers for patients with TRBD. A randomised, double-blind, placebo controlled design is conducted in a naturalistic UK National Health Service setting. An internal pilot study to examine feasibility and acceptability of the study design is included. Participants with TRBD are screened from National Health Service secondary care services in up to 40 mental health trusts in the UK, with the aim of recruiting approximately 414 participants into a pre-randomisation phase to achieve a target of 290 randomised participants. Primary safety and efficacy measures are at 12 weeks following randomisation, with follow up of participants to 52 weeks. The primary outcome is depressive symptoms as measured by Quick Inventory for Depressive Symptomatology - Self Report. Secondary outcomes include changes in anxiety, manic symptoms, tolerability, acceptability, quality of life and cost-effectiveness. Outcome measures are collected remotely using self-report tools implemented online, and observer-rated assessments conducted via telephone. ANCOVA will be used to examine the difference in rating scale scores between treatment arms, and dependent on compliance in completion of weekly self-report measures. A mixed effects linear regression model may also be used to account for repeated measures.

Trial Registration: ISRCTN72151939. Registered on 28 August 2019, http://www.isrctn.com/ISRCTN72151939 Protocol Version: 04-FEB-2021, Version 9.0.
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http://dx.doi.org/10.1186/s12888-021-03322-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256234PMC
July 2021

More than just smoke: Psychopharmacology of cannabinoids.

J Psychopharmacol 2021 Jul 5;35(7):771-772. Epub 2021 Jul 5.

Neuropsychopharmacology Unit, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.

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http://dx.doi.org/10.1177/02698811211028673DOI Listing
July 2021

Early detection of bipolar disorders and treatment recommendations for help-seeking adolescents and young adults: Findings of the Early Detection and Intervention Center Dresden.

Int J Bipolar Disord 2021 Jul 2;9(1):23. Epub 2021 Jul 2.

Department of Psychiatry and Psychotherapy, Carl Gustav Carus University Hospital, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.

Background: Early identification and intervention of individuals with risk factors for or subtle prodromal symptoms of bipolar disorders (BD) may improve the illness course and prevent adverse long-term consequences.

Methods: We examined sociodemographic, clinical and psychopathological characteristics of help-seeking adolescents and young adults who consulted the Early Detection and Intervention Center Dresden at the University of Dresden (Germany) and presented with or without pre-defined at-risk criteria for BD. The standardized diagnostic procedure for all help-seeking youth included a comprehensive psychiatric history and a structured clinical interview. When BD at-risk state was suspected, early detection instruments (EPIbipolar, BPSS-FP) were applied. Treatment recommendations were formulated in multi-professional case conferences.

Results: Out of 890 help-seeking persons between 05/2009 and 04/2018, 582 (65%) completed the diagnostic process. Of these, 24 (4%) had manifest BD and 125 (21%) fulfilled at-risk BD criteria (age = 23.9 ± 0.6 years, female = 62%). Of the pre-defined main risk factors, family history for BD was reported in 22% of the at-risk persons, (hypo-)mania risk state in 44%, and increasing cyclothymic mood swings with increased activity in 48%. The most common secondary risk factors were decreased psychosocial functioning (78%), lifetime diagnosis of depressive disorder (67%) and specific sleep/circadian rhythm disturbances (59%). Substance use was very common in subjects at-risk for BD (cannabis = 50%, alcohol = 33%) and highest in patients with BD (cannabis = 75%, alcohol = 40%). Psychiatric treatment history, including psychopharmacological therapy, was similar between the groups, while treatment recommendations differed, with more advice for psychotherapy and antidepressants in the at-risk group with a lifetime diagnosis of depression and more advice for specialized BD treatment including mood stabilizers in patients with BD.

Conclusion: This analysis on the phenomenology of different BD at-risk stages suggests that early detection of individuals presenting with suggested risk factors for the development of BD is feasible in help-seeking young people. Future research should further develop/test stage-specific prevention and early targeted intervention approaches that were described in a naturalistic setting.
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http://dx.doi.org/10.1186/s40345-021-00227-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253866PMC
July 2021

Development and validation of the Maudsley Modified Patient Health Questionnaire (MM-PHQ-9).

BJPsych Open 2021 Jul 2;7(4):e123. Epub 2021 Jul 2.

Department of Psychological Medicine, Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; and National Service for Affective Disorders, South London and Maudsley NHS Foundation Trust, UK.

Background: The Patient Health Questionnaire-9 (PHQ-9) is a widely used measure of depression in primary care. It was, however, originally designed as a diagnostic screening tool, and not for measuring change in response to antidepressant treatment. Although the Quick Inventory of Depressive Symptomology (QIDS-SR-16) has been extensively validated for outcome measurement, it is poorly adopted in UK primary care, and, although free for clinicians, has licensing restrictions for healthcare organisation use.

Aims: We aimed to develop a modified version of the PHQ-9, the Maudsley Modified PHQ-9 (MM-PHQ-9), for tracking symptom changes in primary care. We tested the measure's validity, reliability and factor structure.

Method: A sample of 121 participants was recruited across three studies, and comprised 78 participants with major depressive disorder and 43 controls. MM-PHQ-9 scores were compared with the QIDS-SR-16 and Clinical Global Impressions improvement scale, for concurrent validity. Internal consistency of the scale was assessed, and principal component analysis was conducted to determine the items' factor structure.

Results: The MM-PHQ-9 demonstrated good concurrent validity with the QIDS-SR-16, and excellent internal consistency. Sensitivity to change over a 14-week period was d = 0.41 compared with d = 0.61 on the QIDS-SR-16. Concurrent validity between the paper and mobile app versions of the MM-PHQ-9 was r = 0.67.

Conclusions: These results indicate that the MM-PHQ-9 is a valid and reliable measure of depressive symptoms in paper and mobile app format, although further validation is required. The measure was sensitive to change, demonstrating suitability for use in routine outcome assessment.
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http://dx.doi.org/10.1192/bjo.2021.953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281039PMC
July 2021

Ceremonial Ayahuasca in Amazonian Retreats-Mental Health and Epigenetic Outcomes From a Six-Month Naturalistic Study.

Front Psychiatry 2021 9;12:687615. Epub 2021 Jun 9.

College of Life and Environmental Sciences, Washington Singer Laboratories, University of Exeter, Exeter, United Kingdom.

Ayahuasca is a natural psychoactive brew, used in traditional ceremonies in the Amazon basin. Recent research has indicated that ayahuasca is pharmacologically safe and its use may be positively associated with improvements in psychiatric symptoms. The mechanistic effects of ayahuasca are yet to be fully established. In this prospective naturalistic study, 63 self-selected participants took part in ayahuasca ceremonies at a retreat centre in the Peruvian Amazon. Participants undertook the Beck Depression Inventory (BDI-II), State-Trait Anxiety Inventory (STAI), Self-compassion Scale (SCS), Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM), as well as secondary measures, pre- and post-retreat and at 6-months. Participants also provided saliva samples for pre/post epigenetic analysis. Overall, a statistically significant decrease in BDI-II (13.9 vs. 6.1, < 0.001), STAI (44.4 vs. 34.3 < 0.001) scores, and CORE-OM scores were observed (37.3 vs. 22.3 < 0.001) at post-retreat, as well as a concurrent increase in SCS (3.1 vs. 3.6, < 0.001). Psychometric improvements were sustained, and on some measures values further decreased at 6-month follow-up, suggesting a potential for lasting therapeutic effects. Changes in memory valence were linked to the observed psychometric improvements. Epigenetic findings were equivocal, but indicated that further research in candidate genes, such as sigma non-opioid intracellular receptor 1 (SIGMAR1), is warranted. This data adds to the literature supporting ayahuasca's possible positive impact on mental health when conducted in a ceremonial context. Further investigation into clinical samples, as well as greater analyses into the mechanistic action of ayahuasca is advised.
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http://dx.doi.org/10.3389/fpsyt.2021.687615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221532PMC
June 2021

Neurocognitive measures of self-blame and risk prediction models of recurrence in major depressive disorder.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jun 24. Epub 2021 Jun 24.

Institute of Psychiatry, Psychology & Neuroscience, Department of Psychological Medicine, Centre for Affective Disorders, King's College London, London, SE5 8AZ, UK; Cognitive and Behavioral Neuroscience Unit, D'Or Institute for Research and Education (IDOR), 22280-080 - Rio de Janeiro, RJ, Brazil; National Service for Affective Disorders, South London and Maudsley NHS Foundation Trust, London SE5 8AZ. Electronic address:

Background: Overgeneralised self-blaming emotions, such as self-disgust, are core symptoms of major depressive disorder (MDD) and prompt specific actions (i.e. "action tendencies"), which are more functionally relevant than the emotions themselves. We have recently shown, using a novel cognitive task, that when feeling self-blaming emotions, maladaptive action tendencies (feeling like "hiding" and like "creating a distance from oneself") and an overgeneralised perception of control are characteristic of MDD, even after remission of symptoms. Here, we probed the potential of this cognitive signature, and its combination with previously employed fMRI measures, to predict individual recurrence risk. For this purpose, we developed a user-friendly hybrid machine-/statistical- learning tool which we make freely available.

Methods: 52 medication-free remitted MDD patients, who had completed the Action Tendencies Task and our self-blame fMRI task at baseline, were followed up clinically over 14-months to determine recurrence. Prospective prediction models included baseline maladaptive self-blame-related action tendencies and anterior temporal fMRI connectivity patterns across a set of fronto-limbic a priori regions of interest, as well as established clinical and standard psychological predictors. Prediction models used elastic-net regularised logistic regression with nested 10-fold cross-validation.

Results: Cross-validated discrimination was highly promising (AuC≥0.86), and positive predictive values over 80% were achieved when including fMRI in multi-modal models, but only up to 71% (AuC≤.74) when solely relying on cognitive and clinical measures.

Conclusions: This shows the high potential of multi-modal signatures of self-blaming biases to predict recurrence risk at an individual level, and calls for external validation in an independent sample.
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http://dx.doi.org/10.1016/j.bpsc.2021.06.010DOI Listing
June 2021

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

Mol Psychiatry 2021 Jun 17. Epub 2021 Jun 17.

Zentrums für Apherese- und Hämofiltration am INUS Tagesklinikum, Cham, Germany.

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.
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http://dx.doi.org/10.1038/s41380-021-01148-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209771PMC
June 2021

Does cognitive improvement translate into functional changes? Exploring the transfer mechanisms of cognitive remediation therapy for euthymic people with bipolar disorder.

Psychol Med 2021 Jun 18:1-9. Epub 2021 Jun 18.

Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Bipolar disorder (BD) is associated with cognitive and functional difficulties, persistent beyond mood episodes. Cognitive remediation (CR) is a psychological therapy targeting cognitive and functioning difficulties. Recent evidence suggests that CR may enhance long-term functioning but transfer mechanisms on functional outcomes have not been explored. We aim to investigate whether and how cognitive gains after CR transfer to functional improvement.

Methods: We considered data from a randomized controlled trial comparing CR (n = 40) to treatment-as-usual (TAU; n = 40) in euthymic people with BD. Treatment outcomes included individual cognitive domains and global cognition, psychosocial functioning, and goal attainment. Regression-based mediation and moderation modelling were used to assess whether and how post-treatment cognitive changes translate into functional improvement at follow-up, three months after treatment end.

Results: Cognitive gains after CR transferred to functional changes three months later: improvement in post-treatment global cognition partially mediated the effect of CR on psychosocial functioning (standardized indirect effect: -0.23, 95% CI -0.51 to -0.04). Goal attainment was not significantly mediated by changes in cognition, but post-treatment cognitive performance moderated the effect of CR on the GAS at follow-up (interaction effect: 0.78, 95% CI 0.08-1.55).

Conclusions: Our findings suggest that cognitive improvements contribute to functional improvement but transfer mechanisms differ between psychosocial functioning and idiosyncratic recovery goals. Cognition accounted for only a proportion of the total CR effect on functional outcomes. Future studies should consider other variables, such as metacognition, that may drive the transfer of CR effects to functional outcomes.
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http://dx.doi.org/10.1017/S0033291721002336DOI Listing
June 2021

Hypothalamic-Pituitary-Adrenal axis dysfunction by early life stress.

Neurosci Lett 2021 08 8;759:136037. Epub 2021 Jun 8.

Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience-King's College London, UK.

Evidence indicates that early life stress (ELS) may act as a risk factor for the development and maintenance of adulthood severe mental health disorders due to persistent dysregulation within the hypothalamic-pituitary-adrenal (HPA) axis. It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. The dysregulation seems to be a byproduct of changes noted in the HPA axis hormone's ability to bind to the glucocorticoid and mineralocorticoid receptors, crucial in maintaining homeostasis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or 'allostasis'. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood This review aims to examine and summarise the existing literature exploring the relationship between ELS with regards specifically to HPA axis functioning. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of HPA hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals.
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http://dx.doi.org/10.1016/j.neulet.2021.136037DOI Listing
August 2021

Resting-state EEG for the diagnosis of idiopathic epilepsy and psychogenic nonepileptic seizures: A systematic review.

Epilepsy Behav 2021 08 3;121(Pt A):108047. Epub 2021 Jun 3.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Camberwell, London SE5 8AB, United Kingdom. Electronic address:

Quantitative markers extracted from resting-state electroencephalogram (EEG) reveal subtle neurophysiological dynamics which may provide useful information to support the diagnosis of seizure disorders. We performed a systematic review to summarize evidence on markers extracted from interictal, visually normal resting-state EEG in adults with idiopathic epilepsy or psychogenic nonepileptic seizures (PNES). Studies were selected from 5 databases and evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. 26 studies were identified, 19 focusing on people with epilepsy, 6 on people with PNES, and one comparing epilepsy and PNES directly. Results suggest that oscillations along the theta frequency (4-8 Hz) may have a relevant role in idiopathic epilepsy, whereas in PNES there was no evident trend. However, studies were subject to a number of methodological limitations potentially introducing bias. There was often a lack of appropriate reporting and high heterogeneity. Results were not appropriate for quantitative synthesis. We identify and discuss the challenges that must be addressed for valid resting-state EEG markers of epilepsy and PNES to be developed.
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http://dx.doi.org/10.1016/j.yebeh.2021.108047DOI Listing
August 2021

Corrigendum to "Journal Metrics in psychiatry: What do the rankings tell us?". Journal of Affective Disorders. 287C (2021) 354- 358.

J Affect Disord 2021 Aug 28;291:416. Epub 2021 May 28.

Louis. A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, 1941 East Rd, Houston, TX 77054. Electronic address:

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http://dx.doi.org/10.1016/j.jad.2021.05.025DOI Listing
August 2021

'Memory, hither come': Psychopharmacology of memory and more.

Authors:
Allan H Young

J Psychopharmacol 2021 Jun 26;35(6):619-620. Epub 2021 May 26.

Division of Academic Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

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http://dx.doi.org/10.1177/02698811211021065DOI Listing
June 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

A retrospective examination of care pathways in individuals with treatment-resistant depression.

BJPsych Open 2021 May 14;7(3):e101. Epub 2021 May 14.

Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Background: Individuals with treatment-resistant depression (TRD) experience a high burden of illness. Current guidelines recommend a stepped care approach for treating depression, but the extent to which best-practice care pathways are adhered to is unclear.

Aims: To explore the extent and nature of 'treatment gaps' (non-adherence to stepped care pathways) experienced by a sample of patients with established TRD (non-response to two or more adequate treatments in the current depressive episode) across three cities in the UK.

Method: Five treatment gaps were considered and compared with guidelines, in a cross-sectional retrospective analysis: delay to receiving treatment, lack of access to psychological therapies, delays to medication changes, delays to adjunctive (pharmacological augmentation) treatment and lack of access to secondary care. We additionally explored participant characteristics associated with the extent of treatment gaps experienced.

Results: Of 178 patients with TRD, 47% had been in the current depressive episode for >1 year before initiating antidepressants; 53% had received adequate psychological therapy. A total of 47 and 51% had remained on an unsuccessful first and second antidepressant trial respectively for >16 weeks, and 24 and 27% for >1 year before medication switch, respectively. Further, 54% had tried three or more antidepressant medications within their episode, and only 11% had received adjunctive treatment.

Conclusions: There appears to be a considerable difference between treatment guidelines for depression and the reality of care received by people with TRD. Future research examining representative samples of patients could determine recommendations for optimising care pathways, and ultimately outcomes, for individuals with this illness.
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http://dx.doi.org/10.1192/bjo.2021.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161596PMC
May 2021

The anterior cingulate cortex as a key locus of ketamine's antidepressant action.

Neurosci Biobehav Rev 2021 08 11;127:531-554. Epub 2021 May 11.

Department of Psychological Medicine, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; South London and Maudsley NHS Foundation Trust, London, United Kingdom.

The subdivisions of the anterior cingulate cortex (ACC) - including subgenual, perigenual and dorsal zones - are implicated in the etiology, pathogenesis and treatment of major depression. We review an emerging body of evidence which suggests that changes in ACC activity are critically important in mediating the antidepressant effects of ketamine, the prototypical member of an emerging class of rapidly acting antidepressants. Infusions of ketamine induce acute (over minutes) and post-acute (over hours to days) modulations in subgenual and perigenual activity, and importantly, these changes can correlate with antidepressant efficacy. The subgenual and dorsal zones of the ACC have been specifically implicated in ketamine's anti-anhedonic effects. We emphasize the synergistic relationship between neuroimaging studies in humans and brain manipulations in animals to understand the causal relationship between changes in brain activity and therapeutic efficacy. We conclude with circuit-based perspectives on ketamine's action: first, related to ACC function in a central network mediating affective pain, and second, related to its role as the anterior node of the default mode network.
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http://dx.doi.org/10.1016/j.neubiorev.2021.05.003DOI Listing
August 2021

Psilocybin: From Serendipity to Credibility?

Front Psychiatry 2021 21;12:659044. Epub 2021 Apr 21.

Department of Psychological Medicine, King's College London, Institute of Psychiatry, Psychology, and Neuroscience, London, United Kingdom.

Psilocybin has a long history of non-medical use and some seem to infer from this that it has therapeutic utility. Early phase clinical trials with psilocybin are encouraging, but suggest only that larger, multicentre trials are required. These are ongoing but will take many years to complete. Meanwhile, retreat centers offering paid experiences with psilocybin truffles have opened in some countries, often using early phase clinical trial data as a basis for bold, public facing claims. This seems unwise. Early phase trials are not designed for their results to be generalized outside the setting they were undertaken in. To do so risks being misleading. Providing what may be seen as an unregulated drug intervention as a paid service is difficult to reconcile with long-held ethical principles underpinning human research and treatment development that were laid down by the 1947 Nuremberg Code and the 1962 Kefauver Harris Amendments. By using psilocybin before it has been properly tested, retreat centers may be undermining their own credibility and the credibility of the wider field.
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http://dx.doi.org/10.3389/fpsyt.2021.659044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096916PMC
April 2021

Antidepressant and antipsychotic treatment of Psychotic Major Depression in a British mental healthcare setting.

J Ment Health 2021 May 7:1-7. Epub 2021 May 7.

Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: Evidence from treatment trials shows that the most effective pharmacological treatment for Psychotic Major Depression (PMD) is combined antidepressant and antipsychotic pharmacotherapy.

Aim: This study investigates the use of antidepressant and antipsychotic treatment for PMD in clinical practice and examines how treatment profiles correlate with demographic and clinical symptoms.

Method: Anonymised electronic health records of 2,837 individuals with PMD were followed up for 12-months post-diagnosis in a historic open cohort design. The use of antidepressants and antipsychotics, alone or in combination, were described using frequency statistics. Demographic and clinical characteristics associated with each treatment were assessed using logistic regression analyses.

Results: Antidepressant and antipsychotic combination pharmacotherapy was the most used treatment for PMD with 69.9% users, compared to antidepressant monotherapy (10.9%) and antipsychotic monotherapy (10.3%). The remaining 8.9% of individuals did not receive antidepressant or antipsychotic treatment. The presence of delusions was strongly associated with the use of antipsychotics, both alone (odds ratio =3.99, 95% confidence intervals = 2.72-5.83, <.001) and in combination with antidepressants (OR = 2.7, 95% CI = 2.09-3.67, <.001), rather than antidepressant treatment alone.

Conclusions: Combined antidepressant and antipsychotic pharmacotherapy is the most common treatment of PMD in clinical practice, showing that clinical practice is in line with evidence from treatment research.
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http://dx.doi.org/10.1080/09638237.2021.1922632DOI Listing
May 2021

Equasy revisited.

Authors:
Allan H Young

J Psychopharmacol 2021 May 3;35(5):499-500. Epub 2021 May 3.

Academic Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

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http://dx.doi.org/10.1177/02698811211012604DOI Listing
May 2021

PRimary carE digital Support ToOl in mental health (PRESTO): Design, development and study protocols.

Rev Psiquiatr Salud Ment 2021 Apr 29. Epub 2021 Apr 29.

Department of Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic de Barcelona, 170 Villarroel st, 12-0, 08036 Barcelona, Catalonia, Spain; Digital Innovation Group, Bipolar and Depressive Disorders Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; University of Barcelona, Barcelona, Catalonia, Spain; Mental Health Research Networking Center (CIBERSAM), Madrid, Spain; Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. Electronic address:

Background: About 30-50% of Primary Care (PC) users in Spain suffer mental health problems, mostly mild to moderate anxious and depressive symptoms, which account for 2% of Spain's total Gross domestic product and 50% of the costs associated to all mental disorders. Mobile health tools have demonstrated to cost-effectively reduce anxious and depressive symptoms while machine learning (ML) techniques have shown to accurately detect severe cases. The main aim of this project is to develop a comprehensive ML digital support platform (PRESTO) to cost-effectively screen, assess, triage, and provide personalized treatments for anxious and depressive symptoms in PC.

Methods: The project will be carried out in 3 complementary phases: First, a ML predictive severity model will be built based on all the cases referred to the PC mental health support programme during the last 5 years in Catalonia. Simultaneously, a smartphone app to monitor and deliver psychological interventions for anxiety and depressive symptoms will be developed and tested in a clinical trial. Finally, the ML models and the app will be integrated in a comprehensive decision-support platform (PRESTO) which will triage and assign to each patient a specific intervention based on individual personal and clinical characteristics. The effectiveness of PRESTO to reduce waiting times in receiving mental healthcare will be tested in a stepped-wedge cluster randomized controlled trial in 5 PC centres.

Discussion: PRESTO will offer timely and personalized cost-effective mental health treatment to people with mild to moderate anxious and depressive symptoms. This will result in a reduction of the burden of mental health problems in PC and on society as a whole.

Trial Registration: The project and their clinical trials were registered in Clinical Trials.gov: NCT04559360 (September 2020).
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http://dx.doi.org/10.1016/j.rpsm.2021.04.003DOI Listing
April 2021

PRimary carE digital Support ToOl in mental health (PRESTO): Design, development and study protocols.

Rev Psiquiatr Salud Ment 2021 Apr 29. Epub 2021 Apr 29.

Department of Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic de Barcelona, 170 Villarroel st, 12-0, 08036 Barcelona, Catalonia, Spain; Digital Innovation Group, Bipolar and Depressive Disorders Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; University of Barcelona, Barcelona, Catalonia, Spain; Mental Health Research Networking Center (CIBERSAM), Madrid, Spain; Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. Electronic address:

Background: About 30-50% of Primary Care (PC) users in Spain suffer mental health problems, mostly mild to moderate anxious and depressive symptoms, which account for 2% of Spain's total Gross domestic product and 50% of the costs associated to all mental disorders. Mobile health tools have demonstrated to cost-effectively reduce anxious and depressive symptoms while machine learning (ML) techniques have shown to accurately detect severe cases. The main aim of this project is to develop a comprehensive ML digital support platform (PRESTO) to cost-effectively screen, assess, triage, and provide personalized treatments for anxious and depressive symptoms in PC.

Methods: The project will be carried out in 3 complementary phases: First, a ML predictive severity model will be built based on all the cases referred to the PC mental health support programme during the last 5 years in Catalonia. Simultaneously, a smartphone app to monitor and deliver psychological interventions for anxiety and depressive symptoms will be developed and tested in a clinical trial. Finally, the ML models and the app will be integrated in a comprehensive decision-support platform (PRESTO) which will triage and assign to each patient a specific intervention based on individual personal and clinical characteristics. The effectiveness of PRESTO to reduce waiting times in receiving mental healthcare will be tested in a stepped-wedge cluster randomized controlled trial in 5 PC centres.

Discussion: PRESTO will offer timely and personalized cost-effective mental health treatment to people with mild to moderate anxious and depressive symptoms. This will result in a reduction of the burden of mental health problems in PC and on society as a whole.

Trial Registration: The project and their clinical trials were registered in Clinical Trials.gov: NCT04559360 (September 2020).
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http://dx.doi.org/10.1016/j.rpsm.2021.04.003DOI Listing
April 2021

Journal Metrics in Psychiatry: What do the rankings tell us?

J Affect Disord 2021 05 19;287:354-358. Epub 2021 Mar 19.

Louis. A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, 1941 East Rd, Houston, TX 77054. Electronic address:

Background: Metrics of journal's impact factor may suggest the journal's influence in a particular field, but they have been used inadvertently as a measure of the journal and individual publications' scientific quality.

Methods: We assessed how scientific journals in the field of psychiatry and mental health are ranked (top 20) according to the scores of distinct metrics (Eigenfactor score, Google Scholar Metrics, Journal Citation Reports, Scimago Journal & Country Rank, and Source Normalized Impact per Paper), described their main characteristics and perfomed a spearman's correlation analyses to investigate to which extent these metrics are associated. We also discussed the limitations of dealing with these metrics and the rankings they provide as a proxy of the journal's quality.

Results: Only 5 (12.5%) journals appear in all metrics (JAMA Psychiatry, American Journal of Psychiatry, Molecular Psychiatry, Schizophrenia Bulletin, and the Journal of Child Psychology and Psychiatry), more than one-third of the journals show up in only one and less than half (42.5%) appear in three or more. Only JAMA Psychiatry is in one of the first five positions of all metrics. No journal ranked in the same position across the metrics. On the other hand, we found the correlations between all the metrics were statistically significant.

Limitations: The metrics included are not exhaustive.

Conclusions: Although each metric provides a particular ranking, they are highly correlated. Rankings also change according to distinct subject categories in which they are assessed. We suggest less emphasis should be given to Journal Metrics to infer journal's quality.
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http://dx.doi.org/10.1016/j.jad.2021.03.039DOI Listing
May 2021

Diet, Obesity, and Depression: A Systematic Review.

J Pers Med 2021 Mar 3;11(3). Epub 2021 Mar 3.

Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, UK.

Background: Obesity and depression co-occur in a significant proportion of the population. Mechanisms linking the two disorders include the immune and the endocrine system, psychological and social mechanisms. The aim of this systematic review was to ascertain whether weight loss through dietary interventions has the additional effect of ameliorating depressive symptoms in obese patients.

Methods: We systematically searched three databases (Pubmed, Medline, Embase) for longitudinal clinical trials testing a dietary intervention in people with obesity and depression or symptoms of depression.

Results: Twenty-four longitudinal clinical studies met the eligibility criteria with a total of 3244 included patients. Seventeen studies examined the effects of calorie-restricted diets and eight studies examined dietary supplements (two studies examined both). Only three studies examined people with a diagnosis of both obesity and depression. The majority of studies showed that interventions using a calorie-restricted diet resulted in decreases in depression scores, with effect sizes between ≈0.2 and ≈0.6. The results were less clear for dietary supplements.

Conclusions: People with obesity and depression appear to be a specific subgroup of depressed patients in which calorie-restricted diets might constitute a promising personalized treatment approach. The reduction of depressive symptoms may be related to immunoendocrine and psychosocial mechanisms.
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http://dx.doi.org/10.3390/jpm11030176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999659PMC
March 2021

Hamlet's augury: how to manage discontinuation of mood stabilizers in bipolar disorder.

Ther Adv Psychopharmacol 2021 15;11:20451253211000612. Epub 2021 Mar 15.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Research has generated good quality evidence about the treatment and management of bipolar disorder in acute and, to some degree, sub-acute/continuation phases. This has informed various guidelines about the treatment and management of bipolar disorder (BD). However, for the long-term or maintenance phase of illness, most guidelines peter out and, in the absence of sufficiently high-quality research evidence, remain vague. This is particularly evident for the important clinical question of discontinuing mood stabilizing pharmacological agents after a period of remission has been achieved. The aim of this review is to put together current existing evidence about discontinuing mood stabilizers after a period of remission in order to come up with a structured and coherent strategy for managing such discontinuation and to make recommendations for future research. To this end, we reviewed the main relevant treatment guidelines and subsequent evidence following the publication of these guidelines. The current recommended long-term treatment of BD is usually considered within the same principles applicable to any chronic health condition (e.g. hypertension or diabetes) where the focus is on continuing treatment at minimum effective medication dose often life-long, switching to alternative choice of medication due to side-effects and very few, if any, indications for complete cessation. However, in the absence of strong evidence on long-term treatment and the high rate of non-concordance in BD, medication discontinuation is a very important aspect of the treatment that should be given due consideration at every aspect of the treatment.
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http://dx.doi.org/10.1177/20451253211000612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968017PMC
March 2021
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