PARP1 and OGG1 in Medicated Patients With Depression and the Response to ECT.

BACKGROUND: Oxidative stress and oxidation-induced DNA damage may contribute to the pathophysiology of depression. Two key mediators of base excision repair (BER) in response to oxidative damage of DNA are OGG1 and PARP1. Few studies have examined changes in OGG1 or PARP1 mRNA in patients with depression or following antidepressant treatment. We examined PARP1 and OGG1 mRNA levels in patients with depression at baseline/pre-electroconvulsive therapy (baseline/pre-ECT) vs in healthy controls and in patients following a course of ECT. METHODS: PARP1 and OGG1 were examined in whole blood samples from medicated patients with depression and controls using quantitative real-time polymerase chain reaction. Exploratory subgroup correlational analyses were performed to determine associations between PARP1 and OGG1 and mood (Hamilton Depression Rating Scale 24-item version) scores as well as with vitamin B3, SIRT1, PGC1α, and tumor necrosis factor alpha levels, as previously reported on in this cohort. RESULTS: PARP1 levels were reduced in samples from patients with depression vs controls (P = .03), though no difference was noted in OGG1. ECT had no effect on PARP1 or OGG1. Higher baseline PARP1 weakly correlated with greater mood improvement post ECT (P = .008). Moreover, PARP1 positively correlated with SIRT1 at baseline and post ECT, and positive correlations were noted between change in PARP1 and change in OGG1 with change in tumor necrosis factor alpha post ECT. CONCLUSIONS: To our knowledge, this is the first study to examine the effect of ECT on BER enzymes. A better understanding of BER enzymes and DNA repair in depression could unearth new mechanisms relevant to the pathophysiology of this condition and novel antidepressant treatments.

Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation.

Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress-CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics.

Mutual support between patients and family caregivers in palliative care: A qualitative study.

BACKGROUND: Patients in receipt of palliative care services are often viewed primarily as recipients of support from their family caregiver. There is a dearth of evidence in palliative care on what comprises mutual support between patients and their family caregivers in palliative care. AIM: To identify processes of mutual support between patients and family caregivers in palliative care. DESIGN: Qualitative study comprising semi-structured interviews. Data were analysed using grounded theory procedures. SETTING/PARTICIPANTS: Fifteen patients with advanced illness (cancer n = 14, neurodegenerative n = 1) and 21 family caregivers recruited from a large regional-based hospice. RESULTS: Mutual support between patients and family caregivers comprised two primary modes in which support was provided and received. Mutual support involved both patients and family caregivers providing similar types of support to each other, and which typically manifested as emotional support. However, mutual support also occurred when patients reciprocated by providing emotional support to their family caregivers to compensate for other forms of support which they felt no longer able to provide. Patients supported family caregivers by involving them in decision-making for care and both patient and family caregiver preferences were influenced by obligation to their respective other. Mutual support comprised both disclosure and concealment. Involving family caregivers in patient care decision-making was intended by patients to help family caregivers adjust to a caregiving role. CONCLUSIONS: The findings inform the development and delivery of psychosocial interventions for patients and family caregivers in palliative care aimed at facilitating supportive relations between them.

Demographic Predictors of Complete Well-Being.

This paper examines demographic differences in flourishing, defined as "complete well-being" and consisting of six domains: emotional health, physical health, purpose, character strengths, social connectedness, and financial security. Results are based on a random, cross-sectional sample of 2363 survey respondents drawn from employees of a large, national, self-insured employer based in the United States. We found that well-being across domains tends to increase with age, although there are some variations. Results are similar across most domains for men and women, although women score higher on character strengths, while men had higher scores on financial security. Racial and ethnic differences were striking. Black employees score higher than the reference group (White employees) on the emotional, purpose, and character strengths domains, but considerably lower on financial security. Hispanics also score lower on financial security (though not as low as Blacks), but higher than Whites on purpose, character strengths, and social connectedness. Asians reported higher well-being than Whites across all domains except purpose.

PBMC telomerase activity in depression and the response to electroconvulsive therapy.

Telomerase, the DNA polymerase responsible for maintaining telomere length, has previously been implicated in depression and the response to antidepressant drugs. In this study, we aimed to compare telomerase activity in peripheral blood mononuclear cells between patients with severe depression recruited as part of the KEEP-WELL Trial (Ketamine for Depression Relapse Prevention Following ECT; NCT02414932) and age- and sex-matched healthy volunteers both at baseline/pre-ECT and at follow-up 1 month later for controls or in patients after a course of ECT. We found no differences in telomerase activity between patients with depression (n = 20) compared to healthy controls (n = 33) at baseline/pre-ECT, or between patients treated with ECT compared to controls at follow-up. In patients, telomerase activity was not associated with mood, as assessed by the 24-item Hamilton Rating Scale for Depression, or the duration of the current depressive episode. Additionally, we found no significant relationship between telomerase activity and exposure to recent or childhood adversity in either the patient or control groups. Overall, our results suggest that telomerase activity is not associated with depression, the therapeutic response to ECT, or exposure to adversity.

Documentation of Do-Not-Attempt-Cardiopulmonary-Resuscitation orders amid the COVID-19 pandemic.

INTRODUCTION: the COVID-19 pandemic has brought the decision-making process regarding cardiopulmonary resuscitation (CPR) into focus. The aim of this study is to compare rates of Do-Not-Attempt-CPR (DNACPR) documentation in older hospitalised patients before and during the COVID-19 pandemic. METHODS: this was a retrospective repeated cross-sectional study. Data including co-morbidities and resuscitation status was collected on 300 patients with COVID-19 hospitalised from 1 March to 31 May 2020. DNACPR documentation rates in patients aged ≥65 years with a diagnosis of COVID-19 were compared to those without COVID-19 admitted during the same period and were also compared to the documentation rates pre-COVID-19 pandemic (1 March-31 May 2019). RESULTS: of 300 COVID-19-positive patients, 28% had a DNACPR order documented during their admission. Of 131 older (≥65 years) patients with COVID-19, 60.3% had a DNACPR order compared to 25.4% of 130 older patients without COVID-19 (P < 0.0001). During a comparable time period pre-pandemic, 15.4% of 130 older patients had a DNACPR order in place (P < 0.0001). Almost fifty percent of DNACPR orders were recorded within 24 h of a positive swab result for SARS-CoV-2. Of older COVID-19-positive patients, 39.2% were referred to palliative care services and 70.2% survived. CONCLUSION: the COVID-19 pandemic has prompted more widespread and earlier decision-making regarding resuscitation status. Although case fatality rates were higher for older hospitalised patients with COVID-19, many older patients survived the illness. Advance care planning should be prioritised in all patients and should remain as part of good clinical practice despite the pandemic.

Mutual support between patients and family caregivers in palliative care: A systematic review and narrative synthesis.

BACKGROUND: Patients in palliative care are usually conceptualised as recipients of support from family caregivers. Family caregivers in palliative care are typically defined as providers of support to patients. Little is known about reciprocal dimensions of support provision between patients and family caregivers in palliative care. AIM: To identify processes of mutual support between patients and family caregivers in palliative care and factors that contribute to or obstruct mutual support between patients and family caregivers in palliative care. DESIGN: Systematic review and narrative synthesis of original peer-reviewed research published between January 2000 and March 2020. DATA SOURCES: Medline, CINAHL, Embase, AMED, PsycINFO and PsycARTICLES. RESULTS: After full-text screening, 10 studies were included. We identified that patients and family caregivers in palliative care can support one another by mutually acknowledging the challenges they face, by remaining positive for one another and by jointly adapting to their changing roles. However, patients and family caregivers may not routinely communicate their distress to each other or reciprocate in distress disclosure. A lack of mutual disclosure pertaining to distress can result in conflict between patients and family caregivers. CONCLUSIONS: Few studies have focused in whole or in part, on reciprocal dimensions of support provision between patients with advancing non-curable conditions, and their family caregivers in palliative care. Further research is required to identify key domains of mutual support between patients and family caregivers in palliative care.

Assessment of the role of FGF15 in mediating the metabolic outcomes of murine Vertical Sleeve Gastrectomy (VSG).

Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its co-morbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in human and its murine orthologue Fgf15 plays a pivotal role in this bile acid driven enterohepatic signaling. The present study evaluated the metabolic outcomes of VSG in Fgf15 deficient mice. 6-8 weeks old male wildtype mice (WT) and Fgf15 deficient mice (KO) were fed a high fat diet (HFD) for 8 weeks. At 8th week of diet, both WT and KO mice were randomly distributed to VSG or sham surgery. Post-surgery, mice were observed for 8 weeks while fed a HFD and then euthanized to collect tissues for experimental analysis. Fgf15 deficient (KO) mice lost weight post VSG, but glucose tolerance in KO mice did not improve post VSG compared to WT mice. Enteroids derived from WT and KO mice proliferated with bile acid exposure in vitro. Post VSG both WT and KO mice had similarly altered bile acid enterohepatic flux, however Fgf15 deficient mice post VSG had increased hepatic accumulation of free and esterified cholesterol leading to lipotoxicity related ER stress, inflammasome activation, and increased Fgf21 expression. Intact Fgf15 mediated enterohepatic bile acid signaling, but not changes in bile acid flux, appear to be important for the metabolic improvements post-murine bariatric surgery. These novel data introduce a potential point of distinction between bile acids acting as ligands compared to their canonical downstream signaling pathways.

Associations between informal care costs, care quality, carer rewards, burden and subsequent grief: the international, access, rights and empowerment mortality follow-back study of the last 3 months of life (IARE I study).

BACKGROUND: At the end of life, formal care costs are high. Informal care (IC) costs, and their effects on outcomes, are not known. This study aimed to determine the IC costs for older adults in the last 3 months of life, and their relationships with outcomes, adjusting for care quality. METHODS: Mortality follow-back postal survey. SETTING: Palliative care services in England (London), Ireland (Dublin) and the USA (New York, San Francisco). PARTICIPANTS: Informal carers (ICrs) of decedents who had received palliative care. DATA: ICrs reported hours and activities, care quality, positive aspects and burdens of caregiving, and completed the Texas Revised Inventory of Grief (TRIG). ANALYSIS: All costs (formal, informal) were calculated by multiplying reported hours of activities by country-specific costs for that activity. IC costs used country-specific shadow prices, e.g. average hourly wages and unit costs for nursing care. Multivariable logistic regression analysis explored the association of potential explanatory variables, including IC costs and care quality, on three outcomes: positive aspects and burdens of caregiving, and subsequent grief. RESULTS: We received 767 completed surveys, 245 from London, 282 Dublin, 131 New York and 109 San Francisco. Most respondents were women (70%); average age was 60 years. On average, patients received 66-76 h per week from ICrs for 'being on call', 52-55 h for ICrs being with them, 19-21 h for personal care, 17-21 h for household tasks, 15-18 h for medical procedures and 7-10 h for appointments. Mean (SD) IC costs were as follows: USA $32,468 (28,578), England $36,170 (31,104) and Ireland $43,760 (36,930). IC costs accounted for 58% of total (formal plus informal) costs. Higher IC costs were associated with less grief and more positive perspectives of caregiving. Poor home care was associated with greater caregiver burden. CONCLUSIONS: Costs to informal carers are larger than those to formal care services for people in the last three months of life. If well supported ICrs can play a role in providing care, and this can be done without detriment to them, providing that they are helped. Improving community palliative care and informal carer support should be a focus for future investment.

Telomere length in depression and association with therapeutic response to electroconvulsive therapy and cognitive side-effects.

BACKGROUND: Electroconvulsive therapy (ECT) is the most acutely effective treatment for severe treatment-resistant depression. However, there are concerns about its cognitive side-effects and we cannot yet confidently predict who will experience these. Telomeres are DNA-protein complexes that maintain genomic integrity. In somatic cells, telomeres shorten with each cell division. Telomere length (TL) can thus provide a measure of 'biological' aging. TL appears to be reduced in depression, though results are mixed. We sought to test the following hypotheses: (1) that TL would be shorter in patients with depression compared to controls; (2) that TL would be a predictor of response to ECT; and (3) that shorter TL would predict cognitive side-effects following ECT. METHOD: We assessed TL in whole blood DNA collected from severely depressed patients (n = 100) recruited as part of the EFFECT-Dep Trial and healthy controls (n = 80) using quantitative real-time polymerase chain reaction. Mood and selected cognitive measures, including global cognition, re-orientation time, and autobiographical memory, were obtained pre-/post-ECT and from controls. RESULTS: Our results indicate that TL does not differ between patients with depression compared to controls. TL itself was not associated with mood ratings and did not predict the therapeutic response to ECT. Furthermore, shorter baseline TL is not a predictor of cognitive side-effects post-ECT. CONCLUSIONS: Overall, TL assessed by PCR does not represent a useful biomarker for predicting the therapeutic outcomes or risk for selected cognitive deficits following ECT.

Tryptophan metabolite concentrations in depressed patients before and after electroconvulsive therapy.

Tryptophan and kynurenine pathway (KP) metabolites are implicated in the pathophysiology of depression. We aimed to investigate their plasma concentrations in medicated patients with depression (n = 94) compared to age- and sex-matched healthy controls (n = 57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting, taking account of co-variables including ECT modality and heterogenous psychopathology. Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D24). Tryptophan (TRP) and kynurenine (KYN) metabolite concentrations [anthranilic acid (AA), 3-hydroxyanthranilic acid (3HAA), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA)] and KYNA/KYN and KYNA/quinolinic acid (QUIN) ratios were lower in patients compared to controls. For the total group there was no significant change in KP metabolites post-ECT or correlations with mood ratings. However, improvements in mood score were correlated with increased KYN, 3-hydroxykynurenine (3HK), 3HAA, QUIN, and KYN/TRP in a subgroup of unipolar depressed patients. Additionally, in remitters baseline KYN, 3HK, and QUIN were associated with baseline HAM-D24 scores, and changes in 3HK and 3HAA concentrations post-ECT correlated with improvement in mood. KYN, KYNA, AA, 3HK, XA, PA, and QUIN were increased in a smaller 3-month follow-up group (n = 19) compared to pre-ECT concentrations. Overall, the results indicate that ECT mobilizes the KP, where a moderate association between selected metabolites and treatment response in unipolar depressed patients is evident.

FXR is a molecular target for the effects of vertical sleeve gastrectomy.

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

Drivers of care costs and quality in the last 3 months of life among older people receiving palliative care: A multinational mortality follow-back survey across England, Ireland and the United States.

BACKGROUND: Care costs rise towards the end of life. International comparison of service use, costs and care experiences can inform quality and improve access. AIM: The aim of this study was to compare health and social care costs, quality and their drivers in the last 3 months of life for older adults across countries. Null hypothesis: no difference between countries. DESIGN: Mortality follow-back survey. Costs were calculated from carers' reported service use and unit costs. SETTING: Palliative care services in England (London), Ireland (Dublin) and the United States (New York, San Francisco). PARTICIPANTS: Informal carers of decedents who had received palliative care participated in the study. RESULTS: A total of 767 questionnaires were returned: 245 in England, 282 in Ireland and 240 in the United States. Mean care costs per person with cancer/non-cancer were US$37,250/US$37,376 (the United States), US$29,065/US$29,411 (Ireland), US$15,347/US$16,631 (England) and differed significantly (F = 25.79/14.27, p < 0.000). Cost distributions differed and were most homogeneous in England. In all countries, hospital care accounted for > 80% of total care costs; community care 6%-16%, palliative care 1%-15%; 10% of decedents used ~30% of total care costs. Being a high-cost user was associated with older age (>80 years), facing financial difficulties and poor experiences of home care, but not with having cancer or multimorbidity. Palliative care services consistently had the highest satisfaction. CONCLUSION: Poverty and poor home care drove high costs, suggesting that improving community palliative care may improve care value, especially as palliative care expenditure was low. Major diagnostic variables were not cost drivers. Care costs in the United States were high and highly variable, suggesting that high-cost low-value care may be prevalent.

Integration of palliative care in services for children with life-limiting neurodevelopmental disabilities and their families: a Delphi study.

BACKGROUND: The aim of this study was to explore expert professionals' opinions on service provision to children under six with life-limiting neurodevelopmental disabilities (LLNDD), including the goals of care and the integration and coordination of palliative care in general and specialist services. METHODS: A Delphi design was used with three questionnaire rounds, one open-ended and two closed response rounds. Primary data collected over a six-month period from expert professionals with five years' (or more) experience in pediatric, intellectual disability and/or palliative care settings. Ratings of agreement and prioritization were provided with agreement expressed as a median (threshold = 80%) and consensus reported as interquartile ranges. Stability was measured using non-parametric tests. RESULTS: Primary goals of care were achievement of best possible quality of life, effective communication and symptom management. Service integration and coordination were considered inadequate, and respondents agreed that areas of deficiency included palliative care. Improvement strategies included a single care plan, improved communication and key worker appointments. CONCLUSIONS: The findings suggest that services do not serve this group well with deficiencies in care compounded by a lack of information on available services and sub-optimal communication between settings. Further research is needed to develop an expert-based consensus regarding the care of children with LLNDD.

Low Circulating Levels of GR, FKBP5, and SGK1 in Medicated Patients With Depression Are Not Altered by Electroconvulsive Therapy.

OBJECTIVES: Hypothalamic-pituitary-adrenal axis dysregulation is frequently observed in patients with depression, with increased levels of the glucocorticoid (GC) cortisol commonly reported. Hypothalamic-pituitary-adrenal axis dysregulation may be a consequence of impaired feedback inhibition due to GC receptor (GR) impairments or dysfunction, termed "glucocorticoid resistance." Here, our objective was to assess mRNA levels of GC-related markers (GR, FKBP5, serum glucocorticoid kinase 1 [SGK1]) in patients with depression versus controls and in patient samples after electroconvulsive therapy (ECT). We also examined the relationship between these GC-related markers and 24-item Hamilton Depression Rating Scale (HAM-D24) scores to assess the utility of using them as biological markers for depression or the therapeutic response to ECT. METHODS: GR, FKBP5, and SGK1 mRNA levels were examined in whole blood samples from 88 medicated patients with depression pre-/post-ECT and 63 controls using quantitative real-time polymerase chain reaction. Exploratory subgroup correlational analyses were performed to determine the relationship between GR, FKBP5, and SGK1 and 24-item Hamilton Depression Rating Scale scores. RESULTS: GR, FKBP5, and SGK1 mRNA levels were significantly lower in medicated patients with depression compared with controls (P < 0.001, P = 0.03, P < 0.001, respectively), but ECT did not alter their levels (all P > 0.05). There was no relationship between GR, FKBP5, or SGK1 and 24-item Hamilton Depression Rating Scale scores. CONCLUSIONS: GR, FKBP5, and SGK1 do not seem to be involved in the peripheral molecular response to ECT and do not represent useful biomarkers for predicting the therapeutic response to ECT in a real-world clinical setting.

Peroxisome proliferator-activated receptor gamma co-activator-1 alpha in depression and the response to electroconvulsive therapy.

BACKGROUND: The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), termed the 'master regulator of mitochondrial biogenesis', has been implicated in stress and resilience to stress-induced depressive-like behaviours in animal models. However, there has been no study conducted to date to examine PGC-1α levels in patients with depression or in response to antidepressant treatment. Our aim was to assess PGC-1α mRNA levels in blood from healthy controls and patients with depression pre-/post-electroconvulsive therapy (ECT), and to examine the relationship between blood PGC-1α mRNA levels and clinical symptoms and outcomes with ECT. METHODS: Whole blood PGC-1α mRNA levels were analysed in samples from 67 patients with a major depressive episode and 70 healthy controls, and in patient samples following a course of ECT using quantitative real-time polymerase chain reaction (qRT-PCR). Exploratory subgroup correlational analyses were carried out to determine the relationship between PGC-1α and mood scores. RESULTS: PGC-1α levels were lower in patients with depression compared with healthy controls (p = 0.03). This lower level was predominantly accounted for by patients with psychotic unipolar depression (p = 0.004). ECT did not alter PGC-1α levels in the depressed group as a whole, though exploratory analyses revealed a significant increase in PGC-1α in patients with psychotic unipolar depression post-ECT (p = 0.045). We found no relationship between PGC-1α mRNA levels and depression severity or the clinical response to ECT. CONCLUSIONS: PGC-1α may represent a novel therapeutic target for the treatment of depression, and be a common link between various pathophysiological processes implicated in depression.

Sex-dependent effects of MC4R genotype on HPA axis tone: implications for stress-associated cardiometabolic disease.

The melanocortin-4 receptor (MC4R) facilitates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress in male rodents and is a well known to regulator of energy balance. Mutations in the MC4R is the most common monogenic cause of obesity in humans and has been associated with sex-specific effects, but whether stress regulation by the MC4R is sex-dependent, and whether the MC4R facilitates HPA responses to chronic stress, is unknown. We hypothesized that MC4R-signaling contributes to HPA axis dysregulation and metabolic pathophysiology following chronic stress exposure. We measured changes in energy balance, HPA axis tone, and vascular remodeling during chronic variable stress (CVS) in male and female rats with MC4R loss-of-function. Rats were placed into three groups (n = 9-18/genotype/sex) and half of each group was subjected to CVS for 30 days or were non-stressed littermate controls. All rats underwent an acute restraint stress challenge on Day 30. Rats were euthanized on Day 31, adrenals collected for weight, and descending aortas fixed for morphological indices of vascular pathophysiology. We observed a marked interaction between Mc4r genotype and sex for basal HPA axis tone and acute stress responsivity. MC4R loss-of-function blunted both endpoints in males but exaggerated them in females. Contrary to our hypothesis, Mc4r genotype had no effect on either HPA axis responses or metabolic responses to chronic stress. Heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females. Lay summary The hypothalamic melanocortin system is an important regulator of energy balance and stress responses. Here, we report a sex-difference in the stress reactivity of rats with a mutation in this system. Our findings highlight how stress may regulate metabolism differently in males and females and may provide insight into sex-differences associated with this mutation in humans.

Ketamine Versus Midazolam for Depression Relapse Prevention Following Successful Electroconvulsive Therapy: A Randomized Controlled Pilot Trial.

OBJECTIVE: Depression relapse after electroconvulsive therapy (ECT) is common (40% at 6 months). Ketamine has a robust antidepressant effect, but there are no reported studies of ketamine for depression relapse prevention. This pilot trial (NCT02414932) was designed to assess feasibility of the proposed trial protocol, including examining reasons for nonrecruitment, nonrandomization, and dropout. METHODS: Patients with unipolar depression referred for ECT were monitored weekly for therapeutic response, using the 24-item Hamilton Rating Scale for Depression (monitoring phase). Those who met standard response criteria were invited to be randomized to a course of 4 once-weekly infusions of ketamine (0.5 mg/kg) or the active comparator, midazolam (0.045 mg/kg), over 40 minutes to examine trial processes (treatment phase). Participants were followed up for 6 months after ECT to assess for relapse. RESULTS: One hundred seventy-five referrals were screened over 18 months, and 68% of eligible participants (n = 43) were recruited to the monitoring phase; 60.5% of participants met ECT response criteria (n = 26), but only 26% (6) of these consented to take part in the treatment phase. These were randomized (3 to ketamine and 3 to midazolam), and no participant completed the 4-week treatment protocol. Information was gathered on reasons for nonrecruitment, nonrandomization, and dropout, which included practical aspects of infusions and lack of interest in further treatment after response to ECT. CONCLUSIONS: The proposed treatment protocol is not suitable for a definitive trial in our center. Information collected on reasons for dropout may inform future clinical trials of intravenous ketamine. TRIAL REGISTRATION: www.clinicaltrials.gov NCT02414932.

Vascular endothelial growth factor plasma levels in depression and following electroconvulsive therapy.

Both animal and human studies have implicated the neurotrophic and angiogenic mediator vascular endothelial growth factor (VEGF) in depression, with meta-analyses, indicating that protein levels are raised in patients with depression. In line with this, we have previously shown that VEGFA mRNA levels are higher in whole blood from patients with depression compared to controls, in particular in patients with psychotic unipolar depression, and that treatment with electroconvulsive therapy (ECT) alters VEGFA mRNA levels. The aim of the present study was, therefore, to extend this previous work by assessing plasma VEGF protein levels in patients with depression compared to healthy controls, and in patients following treatment with ECT. We found that there was no difference between controls and patients with depression with regard to plasma VEGF (p = 0.59), and that VEGF levels were unaltered by ECT (p = 0.09) after correction for potential covariates. We found no correlation between VEGF protein and mRNA levels. Within the subgroup of patients receiving treatment with bitemporal ECT (n = 34), we identified a moderate negative correlation (ρ = - 0.54, p = 0.001) between the change in VEGF and the change in depression severity following treatment; however, no other association between VEGF and mood, responder/remitter status, polarity of depression, or presence of psychosis were found. Overall, our results indicate that the measurement of VEGF protein is not a useful marker for depression or response to treatment, and suggest that the measurement of VEGFA mRNA may prove more useful.

Strategies to address the shortcomings of commonly used advanced chronic heart failure descriptors to improve recruitment in palliative care research: A parallel mixed-methods feasibility study.

BACKGROUND: Recruitment challenges contribute to the paucity of palliative care research with advanced chronic heart failure patients. AIM: To describe the challenges and outline strategies of recruiting advanced chronic heart failure patients. DESIGN: A feasibility study using a pre-post uncontrolled design. SETTING: Advanced chronic heart failure patients were recruited at two nurse-led chronic heart failure disease management clinics in Ireland Results: Of 372 patients screened, 81 were approached, 38 were recruited (46.9% conversion to consent) and 25 completed the intervention. To identify the desired population, a modified version of the European Society of Cardiology definition was used together with modified New York Heart Association inclusion criteria to address inter-study site New York Heart Association classification subjectivity. These modifications substantially increased median monthly numbers of eligible patients approached (from 8 to 20) and median monthly numbers recruited (from 4 to 9). Analysis using a mortality risk calculator demonstrated that recruited patients had a median 1-year mortality risk of 22.7 and confirmed that the modified eligibility criteria successfully identified the population of interest. A statistically significant difference in New York Heart Association classification was found in recruited patients between study sites, but no statistically significant difference was found in selected clinical parameters between these patients. CONCLUSION: Clinically relevant modifications to the European Society of Cardiology definition and strategies to address New York Heart Association subjectivity may help to improve advanced chronic heart failure patient recruitment in clinical settings, thereby helping to address the paucity of palliative care research this population.