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About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS 17 ), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS 17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS 17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite many available treatment options for depression, response rates remain suboptimal. To improve outcome, circadian markers may be suitable as markers of treatment response. This systematic review provides an overview of circadian markers that have been studied as predictors of response in treatment of depression. A search was performed (EMBASE, PUBMED, PSYCHINFO) for research studies or articles, randomized controlled trials and case report/series with no time boundaries on March 2, 2024 (PROSPERO: CRD42021252333). Other criteria were; an antidepressant treatment as intervention, treatment response measured by depression symptom severity and/or occurrence of a clinical diagnosis of depression and assessment of a circadian marker at baseline. 44 articles, encompassing 8,772 participants were included in the analysis. Although additional research is needed with less variation in types of markers and treatments to provide definitive recommendations, circadian markers, especially diurnal mood variation and chronotype, show potential to implement as response markers in the clinic., Competing Interests: Declaration of competing interest SJMD, JHMHH, JK, BCMH, YM, HR and RAS declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Psilocybin is the most researched classic psychedelic for Treatment-Resistant Depression (TRD). While optimizing set and setting are considered essential for efficacy and safety, patient perspectives on these aspects have rarely been investigated. To address this knowledge gap, the current paper explored the experiences of 11 TRD patients (8 women, 3 men) participating in a double-blind randomized clinical trial with a single session of oral (1, 10 or 25 mg) psilocybin treatment. After qualitative analysis, three major themes were identified: (1) challenges with trust-building and expectation management; (2) navigating the experience; and (3) the need for a more comprehensive treatment. Subthemes of the first theme include a general distrust in mental healthcare, trust in study therapists, limited time for preparation, and managing expectations. The second theme included the following subthemes: trusting to surrender, profound and overwhelming experiences, and music as a guide. The third theme addressed a desire for multiple psilocybin sessions, and challenges with sensemaking. Patients' perspectives provided important insights into potential optimization of psilocybin treatment of TRD, including individualized preparation, investment in trust-building, offering additional psilocybin sessions, providing access to sustained (psycho)therapy with trusted therapists, and personalizing treatment approaches, which may also enhance real-world adaption of these treatments., (© 2024. The Author(s).)

Background: Ketamine and its enantiomers are widely researched and increasingly used to treat mental disorders, especially treatment-resistant depression. The phenomenology of ketamine-induced experiences and their relation to its psychotherapeutic potential have not yet been systematically investigated., Aims: To describe the phenomenology of patient experiences during oral esketamine treatment for treatment-resistant depression (TRD) and to explore the potential therapeutic relevance of these experiences., Methods: In-depth interviews were conducted with 17 patients after a 6-week, twice-weekly 'off label' generic oral esketamine (0.5-3.0mg/kg) treatment program. Interviews explored participants' perspectives, expectations, and experiences with oral esketamine treatment. Audio interviews were transcribed and analyzed using an Interpretative Phenomenological Analysis (IPA) framework., Results: The effects of ketamine were highly variable, and psychological distress was common in most patients. Key themes included (a) perceptual effects (auditory, visual, proprioceptive), (b) detachment (from body, self, emotions, and the world), (c) stillness and openness, (d) mystical-type effects (transcendence, relativeness, spirituality), and (e) fear and anxiety. Key themes related to post-session reports included (a) feeling hungover and fatigued, and (b) lifting the blanket: neutralizing mood effects., Conclusion: Patients reported several esketamine effects with psychotherapeutic potential, such as increased openness, detachment, an interruption of negativity, and mystical-type experiences. These experiences deserve to be explored further to enhance treatment outcomes in patients with TRD. Given the frequency and severity of the perceived distress, we identify a need for additional support in all stages of esketamine treatment., (© 2023. The Author(s).)

Insomnia exhibits a clinically relevant relationship with major depressive disorder (MDD). Increasing evidence suggests that insomnia is associated with neurobiological alterations that resemble the pathophysiology of MDD. However, research in a clinical population is limited. The present study, therefore, aimed to investigate the relationship between insomnia and the main pathophysiological mechanisms of MDD in a clinical sample of individuals with MDD. Data were extracted from three cohorts ( N = 227) and included an evaluation of depression severity (Quick Inventory of Depressive Symptomatology, QIDS-SR 16 ) and insomnia severity (QIDS-SR 16 insomnia items) as well as serum and urine assessments of 24 immunologic (e.g., tumour necrosis factor α receptor 2 and calprotectin), neurotrophic (e.g., brain-derived neurotrophic factor and epidermal growth factor), neuroendocrine (e.g., cortisol and aldosterone), neuropeptide (i.e., substance P), and metabolic (e.g., leptin and acetyl-L-carnitine) biomarkers. Linear regression analyses evaluating the association between insomnia severity and biomarker levels were conducted with and without controlling for depression severity ( M = 17.32), antidepressant use (18.9%), gender (59.0% female; 40.5% male), age ( M = 42.04), and the cohort of origin. The results demonstrated no significant associations between insomnia severity and biomarker levels. In conclusion, for the included biomarkers, current findings reveal no contribution of insomnia to the clinical pathophysiology of MDD.

Introduction: Other than for agreement that own mother's milk is the optimum feed, nutritional practice for very preterm babies varies widely. As part of the development of a randomised controlled trial to address preterm nutrition uncertainties, and with the help of the European Foundation for the Care of Newborn Infants (EFCNI), we sought the views of parents across Europe., Methods: We held two roundtable discussions about the proposed trial, inviting the participation of parents and preterm adults through EFCNI. We sought their views and prior knowledge of preterm nutrition uncertainties, treatment comparisons and opinions on specific aspects of design such as cluster versus individual randomisation. We used thematic Framework Analysis to explore the data., Results: There were 11 participants (two men and nine women) from six European countries. Nine were parents and two were preterm adults. Participants strongly supported the need for research to improve care. However, we found little knowledge of methods to resolve uncertainties in care, and wide variation in information provided to parents during their baby's neonatal unit stay. No parent recalled a member of the clinical staff having told them about nutrition uncertainties., Conclusions: Present-day best practice is to involve parents, patients, and the public in all stages of clinical research from design to dissemination and implementation. To strengthen involvement and participation we suggest there is need to improve knowledge of research methods. Clinicians may find it helpful to receive training on how to explain clinical uncertainties, and methods to resolve these., Competing Interests: Declaration of competing interest The EFCNI receives funding from nutrition companies but no co-authors receive any honorarium. NM reports grants from Medical Research Council, grants from National Institute for Health Research, grants from Prolacta Life Sciences, grants from Chiesi International, grants from Westminster Children's Research Trust, grants from European Health Data and Evidence Network, grants from HCA International, grants from Health Data Research UK, grants from Shire Pharmaceuticals, grants from March of Dimes, outside the submitted work. All other authors have no interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants., Methods and Results: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic ® , Olink-Proteomics ® ) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease., Conclusion: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD., Trial Registration: Deutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de ., Impact: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD., (© 2022. The Author(s).)

Background: Ketamine and its enantiomer esketamine represent promising new treatments for treatment-resistant depression (TRD). Esketamine induces acute, transient psychoactive effects. How patients perceive esketamine treatment, and which conditions facilitate optimal outcomes, remains poorly understood. Understanding patient perspectives on these phenomena is important to identify unmet needs, which can be used to improve (es)ketamine treatments., Aims: To explore the perspectives of TRD patients participating in "off label" oral esketamine treatment., Materials and Methods: In-depth interviews were conducted with 17 patients (11 women) after a six-week, twice-weekly esketamine treatment program, and subsequently after six months of at-home use. Interviews explored participants' perspectives, expectations, and experiences with esketamine treatment. Audio interviews were transcribed verbatim and analysed following an Interpretative Phenomenological Analysis (IPA) framework., Results: Key themes included overwhelming experiences; inadequate preparation; letting go of control; mood states influencing session experiences; presence and emotional support, and supportive settings. Patients' attempts to let go and give into vs. attempts to maintain control over occasionally overwhelming experiences was a central theme. Multiple factors influenced patients' ability to give into the experience and appeared to impact their mood and anxiety about future sessions, including level of preparation and education, physical and emotional support, and setting during the session., Conclusion: Better preparation beforehand, an optimized treatment setting, and emotional and psychological support during (es)ketamine sessions can help patients to "let go" and may lead to better quality of care and outcomes. Recommendations to improve quality of patient care in (es)ketamine treatment are provided, including suggestions for the training of nurses and other support staff., Competing Interests: Author RS received a research grant from the Netherlands Organization Health Research and Development for a clinical study on oral esketamine and is the co-investigator of a clinical study on psilocybin funded by Compass Pathways. He has also received an educational grant from Janssen, Pharmaceutical Companies of Johnson and Johnson, and an honorarium from Clexio Biosciences. Author EV was the principal investigator of a clinical trial on MDMA funded by the Multidisciplinary Association for Psychedelic Studies. Author WB has been a consultant for Janssen Netherlands and is a member of the Scientific Advisory Board of Clearmind. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Breeksema, Niemeijer, Kuin, Veraart, Kamphuis, Schimmel, van den Brink, Vermetten and Schoevers.)

Background: Psilocybin is being studied for use in treatment-resistant depression., Methods: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits)., Results: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups., Conclusions: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.)., (Copyright © 2022 Massachusetts Medical Society.)

Ketamine has rapid yet often transient antidepressant effects in patients with treatment-resistant depression. Different strategies have been proposed to prolong these effects. Maintenance ketamine treatment appears promising, but little is known about its efficacy, safety, and tolerability in depression. We searched Pubmed, Embase, and the Cochrane Library and identified three randomised controlled trials, eight open-label trials, and 30 case series and reports on maintenance ketamine treatment. We found intravenous, intranasal, oral, and possibly intramuscular and subcutaneous maintenance ketamine treatment to be effective in sustaining antidepressant effect in treatment-resistant depression. Tachyphylaxis, cognitive impairment, addiction, and serious renal and urinary problems seem uncommon. Despite the methodological limitations, we conclude that from a clinical view, maintenance ketamine treatment seems to be of therapeutic potential. We recommend both controlled and naturalistic studies with long-term follow-up and sufficient power to determine the position of maintenance ketamine treatment within routine clinical practice., Competing Interests: Declaration of interests JKEV received a speaker's fee from Janssen Pharmaceuticals, outside the submitted work. RAS received research funding for two randomised clinical trials with generic oral esketamine from the Netherlands Organisation for Health Research and Development and the National Health Care Institute, a speaker's fee and investigator initiated research grant from Janssen Pharmaceuticals, and consultancy fees from GH Research, Beckley PsyTech, and QPS, outside the submitted work. The other authors declared no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Ketamine is increasingly prescribed for treatment-resistant depression (TRD), often as add-on to regular antidepressants. Augmentation of ketamine to monoamine oxidase inhibitors (MAOIs) is advised against, as this practice might increase blood pressure or cause serotonin syndrome. Despite the potential relevance for patients, little is known about actual side effects of combined use. We summarize literature on the safety and add results of our case series., Evidence Review: PubMed and Embase were searched from inception to July 2021 for English-language articles describing concomitant use of ketamine and MAOIs. The search strategy included terms for "ketamine" AND "monoamine oxidase inhibitor" including generic and brand names. Additionally, we describe the safety of twice weekly oral esketamine administration over the course of 5 weeks to 9 months in 8 TRD patients using MAOIs., Findings: After deduplication, we screened 138 articles and assessed 43 full texts. Twelve studies were included with a total of 39 patients receiving ketamine and MAOIs. Blood pressure and heart rate increased in multiple cases, though this was deemed clinically insignificant in all but 1 patient. No signs of hypertensive crisis or serotonin syndrome were observed. In our case series, we observed minor elevations in blood pressure and heart rate and no serious adverse events., Conclusions and Relevance: The results suggest that combined use of MAOIs and esketamine is less prone to severe side effects than presumed. The investigated sample size was small, and prescribed doses of MAOIs were relatively low. Further research is required before definite conclusions about the safety of this combination can be drawn., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Introduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions., Objective: To systematically review the presence of AEs during and after administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies., Methods: We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies., Results: We included 44 articles (34 quantitative + 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization); no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies., Conclusions: AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder for which dietary interventions can be a useful treatment. In recent years, the low-FODMAP approach is gaining traction in this regard. The fermentation of these non-absorbed carbohydrates by the gut microbiota can generate toxic glycating metabolites, such as methylglyoxal. These metabolites can have harmful effects by their role in the generation of advanced glycation end products (AGEs), which activates Receptor for AGEs (AGER). Mast cells can be stimulated by AGEs and play a role in IBS. We have treated mice with lactose or fructo-oligosaccharides (FOS), with or without co-administration of pyridoxamine and investigated the colonic mucus barrier. We have found that an increased intake of lactose and fructo-oligosaccharides induces a dysregulation of the colonic mucus barrier, increasing mucus discharge in empty colon, while increasing variability and decreasing average thickness mucus layer covering the fecal pellet. Changes were correlated with increased mast cell counts, pointing to a role for the crosstalk between these and goblet cells. Additionally, AGE levels in colonic epithelium were increased by treatment with the selected fermentable carbohydrates. Observed effects were prevented by co-treatment with anti-glycation agent pyridoxamine, implicating glycation processes in the negative impact of fermentable carbohydrate ingestion. This study shows that excessive intake of fermentable carbohydrates can cause colonic mucus barrier dysregulation in mice, by a process that involves glycating agents and increased mucosal mast cell counts., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: The introduction of esketamine into the field of psychiatry comes on the heels of excitement from studies on racemic ketamine. While the intranasal route has been the most studied to date, other modes of administration of esketamine may also be of interest in the management of depression., Aims: To systematically review the literature on non-intranasal esketamine for depression in terms of its antidepressant effect and safety., Methods: We searched PubMed, Embase, the Cochrane Library, and Google Scholar from inception up to February 2021. Search terms included a combination of Medical Subject Headings and text words indicative of esketamine and depression. We selected both controlled and uncontrolled studies examining non-intranasal esketamine for the treatment of depression., Results: We identified four randomized controlled trials (RCTs) on intravenous esketamine and 15 open-label studies on intravenous ( n  = 80), subcutaneous ( n  = 73), and oral ( n  = 5) esketamine. We found intravenous, subcutaneous, and possibly oral administration of esketamine to be effective in reducing depressive symptoms in most patients with major depressive disorder, bipolar depression, and (severe) treatment-resistant depression. Clinical response to repeated administration of esketamine persisted over the course of treatment. Esketamine was well tolerated by most patients, but open-label data indicate marked psychotomimetic symptoms in exceptional cases. The overall quality of the controlled studies was considered high, the overall quality of the uncontrolled studies low to moderate., Conclusions: Intravenous, subcutaneous, and possibly oral esketamine may offer an effective and safe addition to the depression treatment armamentarium. However, as most included studies lacked a control group and had small sample sizes, the quality of our results is limited. Different types and formulations of ketamine remain to be compared directly.

Background: Intravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium., Aims: To explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine., Method: Seven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed., Results: Treatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission., Conclusions: These results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.

Background: Chronotype reflects an individual's optimal daily timing of sleep, activity, and cognitive performance. Previous, cross-sectional, studies have suggested an age effect on chronotype with later chronotypes in adolescents and earlier chronotypes in children and elderly. Additionally, later chronotypes have been associated with more depressive symptoms. Few studies have been able to study longitudinal associations between chronotype and age, while adjusting for depressive symptoms., Methods: Chronotype was assessed twice with the Munich Chronotype Questionnaire 7 years apart in the Netherlands Study of Depression and Anxiety (T1: N = 1842, mean age (SD): 42.63 years (12.66)) and T2: N = 1829, mean age (SD) 50.67 (13.11)). The longitudinal association between change in age and change in chronotype was tested using a generalized estimated equation analysis adjusted for covariates (including level of depressive symptoms). Using age-bins of 5 years (age at T2), change in chronotype between T1 and T2 was analyzed with Linear Mixed Models., Results: We found a change towards an earlier chronotype with higher age (B (95% CI): -0.011 (-0.014-0.008), p < 0.001). For the age-bins, the difference in chronotype was significant for the 25-29 years age-bin., Limitations: The sample did not include individuals younger than 19 years or older than 68 years., Conclusions: In the whole sample chronotype changed towards becoming more morning-type over a period of 7 years, but this change was only significant for those aged 25-29 years. The study was performed in a large naturalistic cohort study with a wide age-range, including patients with a diagnosis of depressive and anxiety disorder and healthy controls., (Copyright © 2021. Published by Elsevier B.V.)

Background: The use of ketamine for depression has increased rapidly in the past decades. Ketamine is often prescribed as an add-on to other drugs used in psychiatric patients, but clear information on drug-drug interactions is lacking. With this review, we aim to provide an overview of the pharmacodynamic interactions between ketamine and mood stabilizers, benzodiazepines, monoamine oxidase-inhibitors, antipsychotics, and psychostimulants., Methods: MEDLINE and Web of Science were searched., Results: Twenty-four studies were included. For lithium, no significant interactions with ketamine were reported. Two out of 5 studies on lamotrigine indicated that the effects of ketamine were attenuated. Benzodiazepines were repeatedly shown to reduce the duration of ketamine's antidepressant effect. For the monoamine oxidase-inhibitor tranylcypromine, case reports showed no relevant changes in vital signs during concurrent S-ketamine use. One paper indicated an interaction between ketamine and haloperidol, 2 other studies did not. Four papers investigated risperidone, including 3 neuroimaging studies showing an attenuating effect of risperidone on ketamine-induced brain perfusion changes. Clozapine significantly blunted ketamine-induced positive symptoms in patients with schizophrenia but not in healthy participants. One paper reported no effect of olanzapine on ketamine's acute psychotomimetic effects., Conclusion: Current literature shows that benzodiazepines and probably lamotrigine reduce ketamine's treatment outcome, which should be taken into account when considering ketamine treatment. There is evidence for an interaction between ketamine and clozapine, haloperidol, and risperidone. Due to small sample sizes, different subject groups and various outcome parameters, the evidence is of low quality. More studies are needed to provide insight into pharmacodynamic interactions with ketamine., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Sleep is crucial for daytime functioning. In populations with psychiatric conditions, many people suffer from insomnia symptoms or an insomnia disorder. Emerging evidence suggests a bidirectional relationship between insomnia and various psychopathologies, implying that insomnia not only may be a consequence of mental disorders but also may contribute to new development, symptom severity, and reoccurrence of diverse mental disorders. Research on potential mechanisms underlying the insomnia psychopathology association is important, both from the preventive and treatment perspective. Most hypotheses concern the influence of insomnia on emotion regulation and on shared pathophysiological pathways, ranging from gut microbiome composition to genetic and specific neurotransmitter system aberrations., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Ketamine shows rapid and robust antidepressant effects in clinical studies. Psychotic features are an exclusion criterion in most ketamine treatment studies based on the assumption that psychosis will increase with ketamine administration. As patients with treatment-resistant depression (TRD) often have psychotic features, and treatment-resistant depressive symptoms are also common in patients with schizophrenia, the aim of this systematic review is to determine whether this assumption holds true., Data Sources: The literature was searched for data on ketamine treatment for depression or negative symptomatology in patients with a history of psychosis or current psychotic symptoms (PubMed/MEDLINE) from inception to March 2020 without date or language restrictions. The following terms were used: ketamine and psychosis, psychotic or schizo* . A filter for human studies was applied., Study Selection: A total of 482 articles were identified; 473 articles were excluded because they did not report on the effect of ketamine treatment in patients with a history of psychosis or current psychotic symptoms., Data Extraction: The remaining 9 articles were reviewed., Results: Nine reports of pilot studies and case reports with a total of 41 patients have been published. These studies suggest that short-term ketamine treatment for depression and even negative symptoms in patients with a history of psychosis or current psychotic features can be both safe and effective, as side effects were mild and self-limiting., Conclusions: The currently available literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients. Data, however, are limited, and further trials are needed in this patient group., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Background: The relative new subspecialty 'cardio-oncology' was established to meet the growing demand for an interdisciplinary approach to the management of cancer therapy-related cardiovascular adverse events. In recent years, specialised cardio-oncology services have been implemented worldwide, which all strive to improve the cardiovascular health of cancer patients. However, limited data are currently available on the outcomes and experiences of these specialised services, and optimal strategies for cardio-oncological care have not been established., Aim: The ONCOR registry has been created for prospective data collection and evaluation of cardio-oncological care in daily practice., Methods: Dutch hospitals using a standardised cardio-oncology care pathway are included in this national, multicentre, observational cohort study. All patients visiting these cardio-oncology services are eligible for study inclusion. Data collection at baseline consists of the (planned) cancer treatment and the cardiovascular risk profile, which are used to estimate the cardiotoxic risk. Information regarding invasive and noninvasive tests is collected during the time patients receive cardio-oncological care. Outcome data consist of the incidence of cardiovascular complications and major adverse cardiac events, and the impact of these events on the oncological treatment., Discussion: Outcomes of the ONCOR registry may aid in gaining more insight into the incidence of cancer therapy-related cardiovascular complications. The registry facilitates research on mechanisms of cardiovascular complications and on diagnostic, prognostic and therapeutic strategies. In addition, it provides a platform for future (interventional) studies. Centres with cardio-oncology services that are interested in contributing to the ONCOR registry are hereby invited to participate.

Background: After stroke, some individuals have latent, propulsive capacity of the paretic leg, that can be elicited during task-specific gait training. The aim of this proof-of-concept study was to investigate the effect of five-week robotic gait training for improving propulsion symmetry by increasing paretic propulsion in chronic stroke survivors., Methods: Twenty-nine individuals with chronic stroke and impaired paretic propulsion (≥ 8% difference in paretic vs. non-paretic propulsive impulse) were enrolled. Participants received ten 60-min sessions of individual robotic gait training targeting paretic propulsion (five weeks, twice a week), complemented with home exercises (15 min/day) focusing on increasing strength and practicing learned strategies in daily life. Propulsion measures, gait kinematics and kinetics, self-selected gait speed, performance of functional gait tasks, and daily-life mobility and physical activity were assessed five weeks (T0) and one week (T1) before the start of intervention, and one week (T2) and five weeks (T3) after the intervention period., Results: Between T0 and T1, no significant differences in outcomes were observed, except for a marginal increase in gait speed (+ 2.9%). Following the intervention, propulsion symmetry (+ 7.9%) and paretic propulsive impulse had significantly improved (+ 8.1%), whereas non-paretic propulsive impulse remained unchanged. Larger gains in propulsion symmetry were associated with more asymmetrical propulsion at T0. In addition, following the intervention significantly greater paretic trailing limb angles (+ 6.6%) and ankle plantarflexion moments (+ 7.1%) were observed. Furthermore, gait speed (+ 7.2%), 6-Minute Walk Test (+ 6.4%), Functional Gait Assessment (+ 6.5%), and daily-life walking intensity (+ 6.9%) had increased following the intervention. At five-week follow-up (T3), gains in all outcomes were retained, and gait speed had further increased (+ 3.6%)., Conclusions: The post-intervention gain in paretic propulsion did not only translate into improved propulsion symmetry and gait speed, but also pertained to performance of functional gait tasks and daily-life walking activity levels. These findings suggest that well-selected chronic stroke survivors may benefit from task-specific targeted training to utilize the residual propulsive capacity of the paretic leg. Future research is recommended to establish simple baseline measures for identification of individuals who may benefit from such training and confirm benefits of the used training concepts in a randomized controlled trial., Trial Registration: Registry number ClinicalTrials.gov ( www.clinicaltrials.gov ): NCT04650802, retrospectively registered 3 December 2020.

Objective: Ketamine has repeatedly shown to have rapid and robust antidepressant effects in patients with treatment resistant depression (TRD). An important question is whether ketamine is as effective and safe as the current gold standard electroconvulsive therapy (ECT)., Methods: The literature was searched for trials comparing ketamine treatment with ECT for depression in the Pubmed/MEDLINE database and Cochrane Trials Library., Results: A total of 137 manuscripts were identified, 6 articles were included in this review. Overall quality of the included studies was diverse with relevant risk of bias for some of the studies. Results suggest that ketamine treatment might give faster but perhaps less durable antidepressant effects. Side effects differed from ECT, in particular less cognitive impairment was apparent in ketamine treatment., Limitations: The included studies have limited sample sizes, use different treatment protocols and in most trials, longer term follow up is lacking. Furthermore, allocation bias appears likely in the non-randomized trials., Conclusions: Current available literature does not yet provide convincing evidence to consider ketamine as an equally effective treatment alternative to ECT in patients with TRD. There are indications for a more favourable short term cognitive side effect profile after ketamine treatment. Methodologically well-designed studies with larger sample sizes and longer follow up duration are warranted., (Copyright © 2020. Published by Elsevier B.V.)

This case report describes successful maintenance treatment with oral S-ketamine in a patient with severe depression, who previously was resistant to electroconvulsive therapy and deep brain stimulation, and who also had comorbid psychotic and obsessive compulsive symptoms., Competing Interests: Competing interests: JKEV received a speaker's honorarium from Janssen, outside the submitted work. RAS has received research funding for two randomised clinical trials with generic oral esketamine from the Netherlands Organisation for Health Research & Development and the National Health Care Institute, a speaker's fee from Janssen and consultancy fee from Clexio Biosciences, both outside the submitted work., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Insomnia and depression are clearly interrelated. Several studies showed that treating insomnia with cognitive behavioural therapy positively affects concurrent depressive symptoms. However, it is unclear what treatment component is responsible for the change in depressive symptoms., Aims: To develop the evidence base we employed a case series design in which we administered a single component sleep restriction treatment to individuals with both insomnia and depressive symptoms., Method: Seven patients were included, of whom six completed the intervention. Patients completed weekly assessments during the 4-week wait period and 6-week treatment phase., Results: At the post-assessment, two out of six patients showed clinical improvement in depressive symptoms. All six patients showed clinically meaningful improvement at the 3-month follow-up assessment, and two patients had maintained gains at 6-month follow-up., Conclusions: This case series study shows that, especially at 3-month follow-up, sleep restriction therapy is associated with clinically relevant treatment gains in patients with both insomnia and depressive symptoms.

Parents and individuals who were born preterm rarely contribute to research study design in order to ensure that outcomes are reported that are of relevance to them. In this article we explore aspects of the measures we use and the lived experiences of three individuals with experience of having a very preterm birth or being very preterm themselves. Their experiences tell us that follow up needs to be more than 2 years, that prematurity needs to be more widely acknowledged in education and that adult services need to consider the consequences of being born early. There are encouraging signs that these important issues are becoming recognised. Individuals designing outcome studies should ensure that these important voices are heard, and their perspectives captured in such studies., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest., (© 2020 Elsevier Ltd. All rights reserved.)

Background: Chronotype is an individual's preferred timing of sleep and activity, and is often referred to as a later chronotype (or evening-type) or an earlier chronotype (or morning-type). Having an evening chronotype is associated with more severe depressive and anxiety symptoms. Based on these findings it is has been suggested that chronotype is a stable construct associated with vulnerability to develop depressive or anxiety disorders. To examine this, we test the stability of chronotype over 7 years, and its longitudinal association with the change in severity of depressive and anxiety symptoms., Methods: Data of 1,417 participants with a depressive and/or anxiety disorder diagnosis and healthy controls assessed at the 2 and 9-year follow-up waves of the Netherlands Study of depression and anxiety were used. Chronotype was assessed with the Munich chronotype questionnaire. Severity of depressive and anxiety symptoms were assessed with the inventory of depressive symptomatology and Beck anxiety inventory., Results: Chronotype was found to be moderately stable (r = 0.53) and on average advanced (i.e., became earlier) with 10.8 min over 7 years (p < .001). Controlling for possible confounders, a decrease in severity of depressive symptoms was associated with an advance in chronotype (B = 0.008, p = .003). A change in severity of anxiety symptoms was not associated with a change in chronotype., Conclusion: Chronotype was found to be a stable, trait-like construct with only a minor level advance over a period of 7 years. The change in chronotype was associated with a change in severity of depressive, but not anxiety, symptoms., (© 2020 The Authors. Depression and Anxiety published by Wiley Periodicals, Inc.)

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available., Competing Interests: Conflict of interest: L. Duijts has nothing to disclose. Conflict of interest: E.R. van Meel has nothing to disclose. Conflict of interest: L. Moschino has nothing to disclose. Conflict of interest: E. Baraldi has nothing to disclose. Conflict of interest: M. Barnhoorn has nothing to disclose. Conflict of interest: W.M. Bramer has nothing to disclose. Conflict of interest: C.E. Bolton has nothing to disclose. Conflict of interest: J. Boyd is an employee of the European Lung Foundation. Conflict of interest: F. Buchvald has nothing to disclose. Conflict of interest: M.J. del Cerro has nothing to disclose. Conflict of interest: A.A. Colin has nothing to disclose. Conflict of interest: R. Ersu has nothing to disclose. Conflict of interest: A. Greenough reports grants and honoraria for lectures from MedImmune/Abbott, outside the submitted work. Conflict of interest: C. Gremmen has nothing to disclose. Conflict of interest: T. Halvorsen has nothing to disclose. Conflict of interest: J. Kamphuis has nothing to disclose. Conflict of interest: S. Kotecha has nothing to disclose. Conflict of interest: K. Rooney-Otero has nothing to disclose. Conflict of interest: S. Schulzke has nothing to disclose. Conflict of interest: A. Wilson has nothing to disclose. Conflict of interest: D. Rigau acts as ERS methodologist. Conflict of interest: R.L. Morgan has nothing to disclose. Conflict of interest: T. Tonia acts as ERS methodologist. Conflict of interest: C.C. Roehr has nothing to disclose. Conflict of interest: M.W. Pijnenburg has nothing to disclose., (Copyright ©ERS 2020.)

Learning motor skills is an essential part of most rehabilitation processes. Facilitating and supporting motor learning is particularly challenging in neurological rehabilitation: patients who suffer from neurological diseases experience both physical limitations and difficulties of cognition and communication that affect and/or complicate the motor learning process. Therapists (e.g. physiotherapists and occupational therapists) who work in neurorehabilitation are therefore continuously searching for the best way to facilitate patients during these intensive learning processes. To support therapists in the application of motor learning, a framework was developed, integrating knowledge from the literature and the opinions and experiences of international experts. This article presents the framework, illustrated by cases from daily practice. The framework may assist therapists working in neurorehabilitation in making choices, implementing motor learning in routine practice, and supporting communication of knowledge and experiences about motor learning with colleagues and students. The article discusses the framework and offers suggestions and conditions given for its use in daily practice.

Background: Studies suggest that light and nature should be seriously considered when building new psychiatric clinics, because of their positive effects on psychiatric recovery.
AIM: To highlight positive and sustainable effects of light and greenery in mental health care.
METHOD: Literature study.
RESULTS: Daylight, artificial light and nature may have a positive influence on recovery and wellbeing of patients and employees in care institutions.
CONCLUSION: Taking light and nature into account in the design of a new psychiatric hospital is highly important. This can facilitate mental health of the users of the building.

Background: Treatment-resistance occurs in about 30% of patients with depression. Therefore, there is an urgent need to identify new treatment strategies. Ketamine, originally developed as an anesthetic, is studied and applied as treatment for patients with treatment-resistant depression.
AIM: A critical review of the current use of ketamine as an antidepressant.
METHOD: Literature study.
RESULTS: Ketamine is a proven effective acute antidepressant. However, limited information is available about maintenance of effect of ketamine, potential risks of repeated administration, and different routes of administration and treatment schedules.
CONCLUSION: Additional research on ketamine as an antidepressant is needed. Meanwhile, (off-label) treatment should only be applied after careful patient selection and under close monitoring.

Background: There is an urgent need to develop additional treatment strategies for patients with treatment-resistant depression (TRD). The rapid but short-lived antidepressant effects of intravenous (IV) ketamine as a racemic mixture have been shown repeatedly in this population, but there is still a paucity of data on the efficacy and safety of (a) different routes of administration, and (b) ketamine's enantiomers esketamine and arketamine. Given practical advantages of oral over IV administration and pharmacodynamic arguments for better antidepressant efficacy of esketamine over arketamine, we designed a study to investigate repeated administration of oral esketamine in patients with TRD., Methods: This study features a triple-blind randomized placebo-controlled trial (RCT) comparing daily oral esketamine versus placebo as add-on to regular antidepressant medications for a period of 6 weeks, succeeded by a follow-up of 4 weeks. The methods support examination of the efficacy, safety, tolerability, mechanisms of action, and economic impact of oral esketamine in patients with TRD., Discussion: This is the first RCT investigating repeated oral esketamine administration in patients with TRD. If shown to be effective and tolerated, oral esketamine administration poses important advantages over IV administration., Trial Registration: Dutch Trial Register, NTR6161. Registered 21 October 2016.

Introduction: Both guided online and individual face-to-face cognitive behavioral therapy for insomnia (CBT-I) are effective in improving insomnia symptoms and sleep efficiency. Little is known about the underlying mechanisms generating this effect. The present study tests the assumption that pre-sleep arousal, sleep-related worry and dysfunctional beliefs about sleep are mediators in the effect of cognitive behavioral treatment for insomnia., Methods: A secondary analysis was performed on data previously collected from a randomized controlled trial (N = 90). In this trial, participants were randomized to either a face-to-face CBT-I condition, an internet-delivered CBT-I condition, or a wait-list group. This article reports on the efficacy of these interventions on pre-sleep arousal, sleep-related worry, and dysfunctional beliefs. Furthermore, we investigated whether these measures mediated the treatment effect on insomnia severity and sleep efficiency., Results: Both treatment modalities were efficacious for these cognitive measures; however, face-to-face treatment showed superiority over the online treatment. All three cognitive measures mediated the effect on insomnia severity. Sleep-related worry and pre-sleep arousal mediated the effect on sleep efficiency, but dysfunctional beliefs did not., Conclusion: Overall, these results point toward the importance of cognitive processes in the treatment of insomnia, implying that psychological treatments for insomnia may best be guided by (also) targeting these cognitive processes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Recent advances in the early detection and treatment of cancer have led to increasing numbers of cancer survivors worldwide. Nonetheless, despite major improvements in the outcome of these patients, long-term side effects of radio- and chemotherapy affect both patient survival and quality of life, independent of the oncological prognosis. Chemotherapy-related cardiac dysfunction is one of the most notorious short-term side effects of anticancer treatment, occurring in ~10% of patients. Progression to overt heart failure carries a strikingly poor prognosis with a 2-year mortality rate of 60%. Early detection of left ventricular damage by periodic monitoring and prompt initiation of heart failure treatment is key in improving cardiovascular prognosis. To meet the growing demand for a specialised interdisciplinary approach for the prevention and management of cardiovascular complications induced by cancer treatment, a new discipline termed cardio-oncology has evolved. However, an uniform, multidisciplinary approach is currently lacking in the Netherlands. This overview provides an introduction and comprehensive summary of this emerging discipline and offers a practical strategy for the outpatient management of this specific patient population.

The colonic mucus barrier is commonly described as a continuous double layer covering the epithelium, separating the microbiota from the intestinal tissue. This model is currently considered valid throughout the colon. The colon is characterised by regional anatomo-functional specificities such as presence and consistency of contents and location. In this study, we characterised the organisation of the colonic mucus barrier in proximal and distal colon of rodents by histological and FISH staining, taking into account aforementioned specificities. By using longitudinal sections and imaging extensive areas of tissue with and without colonic contents, we have obtained a spatiotemporal overview of mucus organisation in the colon. We describe for the first time that the colonic mucus layer covers the faeces instead of the epithelium in the distal colon. This faecal mucus layer confines the microbiota to the faeces and prevents it from remaining in empty distal colon. In the proximal colon, the mucus did not form a separating layer between bacteria and epithelium. We conclude that the organisation of colonic mucus is reliant on the presence of the colonic content, and the location within the colon. Our findings reopen the discussion on the nature of the colonic mucus barrier.

NeuroGUT is a EU-funded initial training network (ITN) of 14 research projects in neurogastroenterology that have employed an equal number of early-stage researchers. Neurogut trainees have-among other activities-attended an international conference on irritable bowel syndrome (IBS) in Bologna in 2016 and were asked to critically review and evaluate the current knowledge on IBS for their respective research activities, and to state what they were missing. Most appreciated were the topics brain imaging of gut activity, the role of the gut microbiota, the pharmacology of gut functions, the IBS-IBD interrelation, the new Rome IV criteria, the role of gas, and the placebo response in functional disorders. Missed were more detailed coverage of high-resolution manometry, functional brain imaging, advanced "systems medicine" approaches and bioinformatics technology, better sub-classification of IBS patients, and the development of disease biomarkers, extended at the molecular (genetic/epigenetic, proteonomic) level. They summarize that despite excellent specialized research, there is a gap open that should be filled with systems medicine. For this, it would be necessary that medical research learns even more from the data sciences and other basic disciplines, for example, information technology and system biology, and also welcomes a change in paradigm that enhances open sharing of data, information, and resources., (© 2016 John Wiley & Sons Ltd.)

Low doses of the antidepressant mirtazapine or the neuroleptic quetiapine are often prescribed off-label for insomnia. However, studies on the effects on sleep and hangover effects the following day are scarce. In this randomised, double-blind, cross-over, placebo-controlled trial, the influence of 7.5 mg mirtazapine and 50 mg quetiapine on both normal sleep and sleep disturbed by acoustic stress (traffic noise) as a model for transient insomnia was assessed. Additionally, hangover effects on next-day alertness and cognitive functioning were examined. A total of 19 healthy men without sleep complaints completed three treatment sessions, each session consisting of three consecutive nights in one of the mirtazapine, quetiapine or placebo conditions. Sleep was assessed using polysomnography and the Leeds Sleep Evaluation Questionnaire. Daytime sleepiness and cognitive functioning were assessed using the Leeds Sleep Evaluation Questionnaire, Karolinska Sleepiness Scale, Digit Symbol Substitution Task, Psychomotor Vigilance Task and an addition task. Under acoustic stress, both mirtazapine and quetiapine increased total sleep time by half an hour and reduced the number of awakenings by 35-40% compared to placebo. While quetiapine specifically increased the duration of non-rapid eye movement sleep, stage N2, mirtazapine mainly increased deep sleep stage N3. Subjects reported that both mirtazapine and quetiapine eased getting to sleep and improved sleep quality. Both drugs caused daytime sleepiness and lessened sustained attention. These findings support the use of low doses of mirtazapine and quetiapine for the treatment of insomnia. Further prospective studies on the long-term effects regarding effectiveness and adverse effects are needed.

Sleep deprivation has profound effects on cognitive performance, and some of these effects may be mediated by impaired prefrontal cortex function. In search of an animal model to investigate this relationship we studied the influence of restricted sleep on operant conditioning in rats, particularly the performance in a differential reinforcement of low rate responding (DRL) task, which is highly dependent upon an intact prefrontal cortex. Animals were trained to withhold a lever press until an imposed delay of 30 s after the last press had passed in order to achieve a food reward. Once the animals had mastered the task, they were sleep-restricted for 7 days with 20 h of sleep deprivation per day. At the end of each daily sleep deprivation session, performance on the DRL task was assessed. The results show that sleep-restricted animals were less able to time their responses correctly, started pressing the lever more randomly and showed signs of behavioural disinhibition, the latter possibly reflecting enhanced impulsivity. Our data support the hypothesis that a sleep debt has disruptive consequences for the functioning of the prefrontal cortex. This model offers possibilities for future studies investigating the underlying biochemical and molecular mechanisms of this relationship., (© 2016 European Sleep Research Society.)

Background/aims: Videocapsule endoscopy (VCE) and double-balloon endoscopy (DBE) allow deep exploration in patients with suspected small bowel pathology. VCE is often performed as an initial small bowel examination to explore whether an intervention by DBE is indicated and to determine insertion route. The study aim was to evaluate the correlation between DBE and VCE in patients with obscure or overt bleeding or anemia, as well as intervention frequency, and complications., Methods: Retrospective observational study., Results: DBE procedures ( n =205) showed small bowel lesions in 64% cases. Antegrade DBE showed positive results in 79% cases, mostly angiodysplasias (63%). Retrograde DBE showed positive results in 22% cases. An intervention was performed in 64% of DBE procedures. The major complication rate was 0.5%, which was one case of perforation. Pancreatitis did not occur. The overall diagnostic agreement was 66% among the 134 DBEs with preceded VCE., Conclusions: In cases of overt or occult bleeding or anemia, DBE was positive in 64%, with only a few complications. Positive correlation was 66% among initially performed VCEs and DBEs. Owing to the time-consuming and invasive character of DBE, performing VCE before DBE might still be clinically relevant., Competing Interests: The authors have no financial conflicts of interest.

Sleep is considered to be a recovery process of prior wakefulness. Not only duration of the waking period affects sleep architecture and sleep EEG, the quality of wakefulness is also highly important. Studies in rats have shown that social defeat stress, in which experimental animals are attacked and defeated by a dominant conspecific, is followed by an acute increase in NREM sleep EEG slow wave activity (SWA). However, it is not known whether this effect is specific for the stress of social defeat or a result of the conflict per se. In the present experiment, we examined how sleep is affected in both the winners and losers of a social conflict. Sleep-wake patterns and sleep EEG were recorded in male wild-type Groningen rats that were subjected to 1h of social conflict in the middle of the light phase. All animals were confronted with a conspecific of similar aggression level and the conflict took place in a neutral arena where both individuals had an equal chance to either win or lose the conflict. NREM sleep SWA was significantly increased after the social conflict compared to baseline values and a gentle stimulation control condition. REM sleep was significantly suppressed in the first hours after the conflict. Winners and losers did not differ significantly in NREM sleep time, NREM sleep SWA and REM sleep time immediately after the conflict. Losers tended to have slightly more NREM sleep later in the recovery period. This study shows that in rats a social conflict with an unpredictable outcome has quantitatively and qualitatively largely similar acute effects on subsequent sleep in winners and losers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Generalized slowing characterizes aging and there is some evidence to suggest that this slowing already starts at midlife. This study aims to assess reaction time changes while performing a concurrent low-force and high-force motor task in young and middle-aged subjects. The high-force motor task is designed to induce muscle fatigue and thereby progressively increase the attentional demands. Twenty-five young (20-30 years, 12 males) and 16 middle-aged (35-55 years, 9 males) adults performed an auditory two-choice reaction time task (CRT) with and without a concurrent low- or high-force motor task. The CRT required subjects to respond to two different stimuli that occurred with a probability of 70 or 30%. The motor task consisted of index finger abduction, at either 10% (10%-dual-task) or 30% (30%-dual-task) of maximal voluntary force. Cognitive task performance was measured as percentage of correct responses and reaction times. Middle-aged subjects responded slower on the frequent but more accurately on the infrequent stimuli of CRT than young subjects. Both young and middle-aged subjects showed increased errors and reaction times while performing under dual-task conditions and both outcome measures increased further under fatiguing conditions. Only under 30%-dual-task demands, an age-effect on dual-task performance was present. Both single- and dual-task conditions showed that already at mid-life response preparation is seriously declined and that subjects implement different strategies to perform a CRT task.

Psychiatric disorders are often associated with disturbed sleep. Poor sleep can attenuate emotional control, including the regulation of aggression, and thus, may increase the risk of impulsive, aggressive acts. This cross-sectional study aimed to investigate the potential contribution of sleep problems to subjective and objective aggressiveness and impulsivity in a forensic psychiatric population. Questionnaires on sleep quality (Pittsburgh Sleep Quality Index), chronic severe insomnia (Sleep Diagnosis List), aggressiveness (Aggression Questionnaire) and impulsivity (Barratt Impulsiveness Scale-11) were completed by 96 forensic psychiatric inpatients, admitted to two forensic facilities in the Netherlands. To obtain more objective measurements of aggression and impulsivity, observational scores on a professional instrument to assess the risk of future aggression (Historical Clinical Future-30) and reported aggressive incidents were collected from files. Results showed that a worse sleep quality and higher insomnia scores were significantly associated with self-reported aggression and impulsivity, clinician-rated hostility and involvement in aggressive incidents within the facility. Whether a participant was professionally judged as impulsive could not be predicted by sleep quality or the insomnia score. To a large extent the results of this study support the hypothesis that poor sleep is related to impulsive, aggressive behavior in forensic psychiatric patients. It is worthwhile to examine the protective effect of treatment of sleep difficulties on aggressive reactivity in (forensic) psychiatric populations., (© 2013 Elsevier Inc. All rights reserved.)

Objective: Poor sleep is known to cause detrimental effects on the course of diverse psychiatric disorders and is a putative risk factor for hostility and aggression. Thus, sleep may be crucial in forensic psychiatric practice. However, little is known about the prevalence of sleep disturbances in these complex psychiatric patients., Methods: In this study we investigated the presence of sleep disorders and subjective sleep quality using the Sleep Diagnosis List (SDL), the Pittsburgh Sleep Quality Index (PSQI), interviews addressing the causes of sleep complaints, and file information on sleep medications in 110 patients admitted to a forensic psychiatric hospital., Results: Almost 30% of the participants suffered from one or more sleep disorders, especially insomnia. An even larger proportion of the participants (49.1%) experienced poor sleep quality. Interestingly, patients with an antisocial personality disorder or traits were particularly dissatisfied with their sleep. The most common causes of sleep problems were suboptimal sleep hygiene, stress or ruminating, negative sleep conditioning, and side effects of psychotropic medication. Of the poor sleepers, 40.7% received a hypnotic drug., Conclusion: Despite intensive clinical treatment, sleep problems are experienced by a large number of forensic psychiatric patients. It would be worthwhile to examine the effects of pharmacological and non-pharmacological sleep interventions on both psychiatric symptoms and reactive aggressive behavior in forensic patients., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Using the concept map method, this study aimed to summarize and describe patient characteristics pertinent to treatment selection for patients with personality disorders (PDs). Initial patient characteristics were derived from the research literature and a survey among Dutch expert clinicians. Concept mapping is a formalized conceptualization procedure that describes the underlying cognitive structures people use in complex tasks, such as treatment allocation. Based on expert opinions of 29 Dutch clinicians, a concept map was generated that yielded eight domains of patient characteristics, i.e., Severity of symptoms, Severity of personality pathology, Ego-adaptive capacities, Motivation and working alliance, Social context, Social demographic characteristics, Trauma, and Treatment history and medical condition. These domains can be ordered along two bipolar axes, running from internal to external concepts and from vulnerability to strength concepts, respectively. Our findings may serve as input for the delineation of algorithms for patient-treatment matching research in PD.

Clinical observations suggest that sleep problems may be a causal factor in the development of reactive aggression and violence. In this review we give an overview of existing literature on the relation between poor sleep and aggression, irritability, and hostility. Correlational studies are supporting such a relationship. Although limited in number, some studies suggest that treatment of sleep disturbances reduces aggressiveness and problematic behavior. In line with this is the finding that sleep deprivation actually increases aggressive behavior in animals and angriness, short-temperedness, and the outward expression of aggressive impulses in humans. In most people poor sleep will not evoke actual physical aggression, but certain individuals, such as forensic psychiatric patients, may be particularly vulnerable to the emotional dysregulating effects of sleep disturbances. The relation between sleep problems and aggression may be mediated by the negative effect of sleep loss on prefrontal cortical functioning. This most likely contributes to loss of control over emotions, including loss of the regulation of aggressive impulses to context-appropriate behavior. Other potential contributing mechanisms connecting sleep problems to aggression and violence are most likely found within the central serotonergic and the hypothalamic-pituitary-adrenal-axis. Individual variation within these neurobiological systems may be responsible for amplified aggressive responses induced by sleep loss in certain individuals. It is of great importance to identify the individuals at risk, since recognition and adequate treatment of their sleep problems may reduce aggressive and violent incidents., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Lack of self-esteem may play an important role in the development of eating disorders (ED). This study investigated the differential impact of positive and negative feedback on implicit and explicit self-esteem in women with an ED (N=25) as compared to women without an ED (N=29)., Method: False feedback (positive or negative) was given on participant's performance on a specifically developed intellectual test. Before and after the performance, explicit and implicit self-esteem was measured., Results: On the explicit measure ED patients reacted congruently with the nature of the feedback. On the implicit measure only ED patients responded to the positive feedback with an improvement of self-esteem, with no effect for negative feedback. The control group was unaffected by either feedback. Furthermore, no correlation was observed between the explicit and implicit measures, a finding suggesting that these measurements tap different constructs., Conclusion: Positive feedback affects implicit self-esteem of female patients with eating disorders. The results underline the importance of positively approaching women with ED.

Are there limits to the duration of high quality of life? Are there limits to healthy life for a human brain? We have had the opportunity to evaluate the performance of a 112-113-year-old woman and perform full pathological examination of her body immediately after death at the age of 115. The psychological tests revealed that her general performance was above average of healthy adults of 60-75 years. The pathological observations revealed almost no atherosclerotic changes throughout the body. In the brain almost no beta-amyloid plaques or vascular changes were found and only slight accumulation of hyperphosphorylated tau protein with a Braak-stage 2. Counts of the number of locus coeruleus neurons corresponded with the number of neurons found in the brains of healthy people of 60-80 years old. Our observations indicate that the limits of human cognitive function extends far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentanarians, is not inevitable.