Case report: delayed response after electroconvulsive therapy in a patient with major depressive disorder.

BACKGROUND: Major depressive disorder and associated mood syndromes are amongst the most common psychiatric disorders. To date, electroconvulsive therapy (ECT) is considered the most effective short-term treatment for patients with severe or treatment-resistant depression. In clinical practice, there is considerable variation in the ECT dosing schedule, with the number of sessions typically ranging from 6 to 12, with early antidepressant effects being predictive of increased positive outcomes. We describe here an unusual case of a female patient with severe depression who did not respond to ECT until the 11th session, after which she had shown a drastic improvement in her mental state. CASE PRESENTATION: A 75-year-old female presented to the old age psychiatry inpatient unit with new onset dysphoric mood, anhedonia, and severe negativity. She scored 23 on the 17-item Hamilton Rating Scale for Depression (HAM-D), and was rated 6 on Clinical Global Impression severity (CGIS) by the responsible clinician. She suffered from post-natal depression fifty years ago and was successfully treated with ECT. She was therefore initiated on a course of ECT treatment. Her condition initially deteriorated, displaying features of catatonia and psychosis, unresponsive to ECT treatment or concurrent psychotropic medications. After 11th ECT session, she started to show signs of clinical improvement and returned close to her baseline mental state after a total of 17 ECT sessions. She remained well 3 months post-treatment, scoring 4 on HAM-D, Clinical Global Improvement or change (CGI-C) rated as 1 (very much improved). The diagnosis was ICD-10 F32.3 severe depressive episode with psychotic symptoms. CONCLUSIONS: we describe here an unusual case of delayed response to electroconvulsive therapy in the treatment of severe depressive disorder. Studies have shown the number of acute ECT treatments to be highly variable, affected by a number of factors including treatment frequency, condition treated and its severity, the ECT technical parameters, as well as concurrent use of pharmacological treatment. This may call for re-consideration of the current ECT treatment guidelines, requiring more research to help stratify and standardize the treatment regime

Predicting patients with dementia most at risk of needing psychiatric inpatient or enhanced community care using routinely collected clinical data: a retrospective multi-site cohort study

BACKGROUND. Dementia is a common and progressive condition whose prevalence is grow-ing worldwide. It is challenging for healthcare systems to provide continuity in clinical ser-vices for all patients from diagnosis to death. AIMS. To test whether patients who are most likely to need enhanced support later in the disease course can be identified at the point of diagnosis, thus allowing the targeted intervention. METHOD. We used clinical information collected routinely in de-identified electronic patient records from two United Kingdom NHS Trusts to identify at diagnosis which patients were at increased risk of needing enhanced care (psychiatric inpatient or intensive (crisis) community care). RESULTS. We examined the records of a total of 27,313 patients with dementia. A minority (16% in Cambridgeshire and 2.4% in London) needed enhanced care. Patients who needed enhanced care differed from those who did not in age, cognitive test scores, and Health of the Nation Outcome Scale scores. Logistic regression discriminated risk with an area under the receiver operating char-acteristic curve (AUROC) of up to 0.78 after 1 year and 0.74 after 4 years. We were able to confirm the validity of the approach in two Trusts which differed widely in the populations they serve. CONCLUSIONS. It is possible to identify, at the time of diagnosis of dementia, pa-tients most likely to need enhanced care later in the disease course. This permits the devel-opment of targeted clinical interventions for this high-risk group

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Case report: delayed response after electroconvulsive therapy in a patient with major depressive disorder.

BACKGROUND: Major depressive disorder and associated mood syndromes are amongst the most common psychiatric disorders. To date, electroconvulsive therapy (ECT) is considered the most effective short-term treatment for patients with severe or treatment-resistant depression. In clinical practice, there is considerable variation in the ECT dosing schedule, with the number of sessions typically ranging from 6 to 12, with early antidepressant effects being predictive of increased positive outcomes. We describe here an unusual case of a female patient with severe depression who did not respond to ECT until the 11th session, after which she had shown a drastic improvement in her mental state. CASE PRESENTATION: A 75-year-old female presented to the old age psychiatry inpatient unit with new onset dysphoric mood, anhedonia, and severe negativity. She scored 23 on the 17-item Hamilton Rating Scale for Depression (HAM-D), and was rated 6 on Clinical Global Impression severity (CGIS) by the responsible clinician. She suffered from post-natal depression fifty years ago and was successfully treated with ECT. She was therefore initiated on a course of ECT treatment. Her condition initially deteriorated, displaying features of catatonia and psychosis, unresponsive to ECT treatment or concurrent psychotropic medications. After 11th ECT session, she started to show signs of clinical improvement and returned close to her baseline mental state after a total of 17 ECT sessions. She remained well 3 months post-treatment, scoring 4 on HAM-D, Clinical Global Improvement or change (CGI-C) rated as 1 (very much improved). The diagnosis was ICD-10 F32.3 severe depressive episode with psychotic symptoms. CONCLUSIONS: we describe here an unusual case of delayed response to electroconvulsive therapy in the treatment of severe depressive disorder. Studies have shown the number of acute ECT treatments to be highly variable, affected by a number of factors including treatment frequency, condition treated and its severity, the ECT technical parameters, as well as concurrent use of pharmacological treatment. This may call for re-consideration of the current ECT treatment guidelines, requiring more research to help stratify and standardize the treatment regime

The epidemiology and clinical features of personality disorders in later life; a study of secondary care data.

Funder: NIHR Applied Research CentreOBJECTIVES: Personality disorders (PDs) are often conceptualised as impacting individuals throughout their life. However, there has been limited study of the disorders in those over the age of 65. We have used the psychiatric secondary care medical records of 21,971 individuals over the age of 65 from Cambridgeshire, UK, who received care between 2014 and 2021 to characterise older patients with a PD diagnosis. METHODS: The data from all patients >65 with a diagnosis of personality disorder (PD) was extracted (n = 217) along with two comparison groups (n = 2170); patients 65 with a psychiatric diagnosis other than PD or dementia. RESULTS: Compared to younger patients with PD, older patients were more likely to be male, married, suffering from a mixed PD and live in less deprived areas. Compared to patients >65 with diagnoses other than PD, older patients were more likely to be female, single or divorced and had a higher level of social deprivation. Our most striking finding was that older patients with PDs were more likely to experience polypharmacy. A mean of 18.48 different drugs had been prescribed over their lifetime, compared to 9.51 for patients >65 with other mental health diagnoses. CONCLUSION: Here we present the largest ever description of this group of patients and provide insights that could inform clinical practice and future research

Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.

Funder: Wellcome TrustDementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed-particularly any that can slow down the disease's progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents-in particular the licensed antidepressant trazodone-and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) (JOB). UK Dementia Research Institute (funded by the Medical Research Council UK, Alzheimer's Research UK and the Alzheimer's Society) (G.R.M., H.S.), the Cambridge Centre for Parkinson-Plus (G.R.M. and A.B.) the European Research Council (consolidator grant UPR Neuro; no. 647479), the Joint Proramme Neurodegenerative Disease, the Centres of Excellence in Neurodegeneration and the Well come Trust Collaborative Award (G.R.M). Gnodde Goldman Sachs Translational Neuroscience (B.U &E.S

Trazodone and patient outcomes in dementia-Limitations of naturalistic cohort data.

The unfolded protein response has been increasingly implicated as an important pathological pathway and target for therapeutic intervention in neurodegeneration. The licensed antidepressant trazodone is one drug which has been proposed to act on this pathway and may therefore be a potential therapy. Previous examination of existing data for patients with dementia prescribed trazodone did not find a signal suggesting a disease modifying effect. Here we add to that literature by examining the electronic patient record of patients with dementia in Cambridgeshire UK. We found that trazodone is rarely prescribed and where it is used it is at a dose less than half that predicted to be disease modifying. We also found that patients prescribed trazodone had higher levels of neuropsychiatric symptoms and were relatively late in the disease course, likely beyond the optimal point for therapeutic intervention. We suggest it is therefore premature to discard potential therapies based on observational data alone, particularly when experimental medicine approaches to examine the effects of trazodone are feasible

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom.

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency