DNA methylation of serotonin genes as predictive biomarkers of antidepressant treatment response.

Selective serotonin reuptake inhibitors (SSRI) are frequently ineffective in treating depressive episodes and biomarkers are needed to optimize antidepressant treatment outcomes. DNA methylation levels of serotonin transporter (SLC6A4) and tryptophan hydroxylase 2 genes (TPH2) have been suggested to predict antidepressant clinical outcomes but their applicability remains uncertain. In this study, we: 1) evaluated SLC6A4/TPH2 methylation biomarker potential for predicting clinical outcomes after escitalopram treatment; 2) evaluated whether changes in SLC6A4/TPH2 methylation are informative of treatment mechanisms. We used a cohort of 90 unmedicated patients with major depressive disorder that were part of a 12-week open-label longitudinal trial and compared our observations with previous findings. Depressive symptoms were measured at baseline and after 8 and 12 weeks of treatment using the Hamilton Depression Rating Scale (HAMD6/17). We found an association between baseline TPH2 methylation and both clinical response (ß:3.43; p = 0.01; 95 % CI:[0.80; 6.06]) and change in depressive symptoms after 8 weeks (ß:-45.44; p = 0.01; 95 %CI:[- -78.58; -12.30]). However, we found no evidence for predictive value of any gene (TPH2 AUC: 0.74 95 % CI:[0.42;0.79]; SLC6A4: AUC: 0.61; 95 % CI: [0.48-0.78]). Methylation levels changed at the trend level for CpG sites of SLC6A4 and TPH2 over the course of 12 weeks of treatment. In addition, similar to previous observations, we found a trend for an association between methylation of SLC6A4 CpG2 (chr17:30,236,083) and HAMD17 change after 12 weeks. Our findings suggest that although TPH2 and SLC6A4 methylation may be informative of antidepressant treatment outcome, they are unlikely to prove useful as clinical predictor tools.

Effects of cognitive training under hypoxia on cognitive proficiency and neuroplasticity in remitted patients with mood disorders and healthy individuals: ALTIBRAIN study protocol for a randomized controlled trial.

BACKGROUND: Cognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects. METHODS: In sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [11C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region. DISCUSSION: The results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06121206 . Registered on 31 October 2023.

Associations of benzodiazepine use with cognitive ability and age-related cognitive decline.

BACKGROUND: It remains uncertain whether long-term use of benzodiazepines is associated with age-related cognitive decline, and if cognitive ability in early life is the driver of any association. This study examines the association of cognitive ability in young adulthood with later use of benzodiazepines and explores whether the use of benzodiazepines during adult life is associated with cognitive decline in late midlife. METHODS: The study samples include cognitive tests on the Børge Priens Prøve (BPP) from the conscription board examination (age 19 years) from 335 513 men born 1949-1961 and data from re-examinations of 5183 men 44 years later. Cognitive decline was defined as the difference between scores at the conscription board and the re-examination. Information on purchases of benzodiazepines was obtained from the Danish National Prescription Registry, 1995-2022. Associations were analysed using Cox proportional hazards and linear regression. RESULTS: In total, 120 911 (36%) men purchased benzodiazepines during a follow-up of 20 years. Lower cognitive scores in young adulthood were associated with a higher risk of initiating benzodiazepines (hazard ratio [95% CI] = 0.71[0.68-0.75]). Men with the highest cumulative use of benzodiazepines had larger cognitive decline (ß-coefficient [95% CI] = -1.66 [-2.09 to -1.23] BPP scores) compared with never users. Current benzodiazepine users showed a larger cognitive decline than never users (ß-coefficient [95% CI] = -2.42[-3.18 to -1.66] BPP scores) and this partially explained the above association. These estimates for cognitive decline were relatively small and may lack clinical relevance. CONCLUSION: Low cognitive ability increases the risk of benzodiazepine use in adulthood and cognitive decline is more pronounced in those with the highest benzodiazepine use compared with never-use, but the difference lacks clinical significance.

Clinical Outcomes of Continuation and Maintenance Electroconvulsive Therapy.

Importance: Large-scale evidence for the efficacy of continuation and maintenance electroconvulsive therapy (c/mECT) is lacking. Objective: To provide an exhaustive and naturalistic insight into the real-world outcomes and the cost-effectiveness of c/mECT in a large dataset. Design, Setting, and Participants: This cohort study included all patients in the Danish National Patient Registry who initiated treatment with ECT from 2003 through 2022. The data were analyzed from October 2023 to February 2024. Exposures: ECT. An algorithm to identify c/mECTs in the dataset was developed: (>3 treatments with ≥7 and <90 days between adjacent treatments, occurring within a time frame of 180 days [cECT] or more [mECT] after an acute [aECT] series). Main Outcomes and Measures: The association of c/mECT with subsequent 6- to 12-month risk of hospitalization or suicidal behavior using Cox proportional hazard regression with multiple adjustments and aECT only as a reference, propensity score matching, and self-controlled case series analysis using a Poisson regression model. A cost-effectiveness analysis based on hospitalization and ECT expenses was made. Results: A total of 19 944 individuals were treated with ECT (12 157 women [61%], 7787 men [39%]; median [IQR] age, 55 [41-70] years). Of these, 1533 individuals (7.7%) received c/mECT at any time point (1017 [5.1%] cECT only and 516 [2.6%] mECT). Compared with patients receiving aECT only, c/mECT patients more frequently experienced schizophrenia (odds ratio [OR], 2.14; 95% CI, 1.86-2.46) and schizoaffective disorder (OR, 2.42; 95% CI, 1.90-3.09) and less frequently unipolar depression (OR, 0.56; 95% CI, 0.51-0.62). In all models, c/mECT was associated with a lower rate of hospitalization after finishing aECT (eg, 6-month adjusted hazard ratio, 0.68; 95% CI, 0.60-0.78 [Cox regression]; 6-month incidence rate ratio, 0.51; 95% CI, 0.41-0.62 [Poisson regression]). There was no significant difference in the risk of suicidal behavior. Compared with the periods before the end of aECT, c/mECT was associated with a substantial reduction in total treatment costs. Conclusions and Relevance: In a nationwide and naturalistic setting, c/mECT after aECT was infrequently used but associated with a lower risk of readmission than aECT alone. The totality of the evidence indicates that c/mECT should be considered more often to prevent relapse after successful aECT in patients whose condition does not respond sufficiently to other interventions.

Effect of antidepressant treatment on 5-HT4 receptor binding and associations with clinical outcomes and verbal memory in major depressive disorder.

BACKGROUND: Brain serotonin 4 receptor (5-HT4R) levels are lower in untreated patients with Major Depressive Disorder (MDD) and are linked to verbal memory. We here investigate the relationship between 5-HT4R, clinical outcomes, and cognitive function in patients with MDD who initiate SSRI drug treatment. METHODS: Ninety moderately to severely depressed patients underwent molecular brain imaging to measure 5-HT4R binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HT4R binding was assessed for its ability to predict treatment outcome at week 4, 8 or 12. In 40 patients rescanned 8 weeks post treatment, the change in cerebral 5-HT4R binding was correlated to change in verbal memory and to change in depressive symptoms, as evaluated by the Hamilton Depressive Rating Scale 6 (HAMD6). RESULTS: After 8 weeks of serotonergic intervention neostriatal 5-HT4R binding was reduced by 9%. Global change in 5-HT4R binding from baseline was associated with verbal memory outcomes, but not with overall clinical depressive symptom outcomes. Pretreatment 5-HT4R binding did not predict clinical recovery status at week 8, nor was it associated with change in HAMD6. CONCLUSIONS: In patients with moderate to severe MDD, treatment with SSRI's downregulates neostriatal 5-HT4R levels, consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT4R levels are downregulated after SSRIs, the more verbal memory improves, highlighting the potential importance of 5-HT4R as a treatment target in MDD. The findings offer insights to mechanisms underlying antidepressant effects and point to new directions for precision medicine treatments for MDD.

Perturbation-based balance training of older adults and effects on physiological, cognitive and sociopsychological factors: a secondary analysis from a randomised controlled trial with 12-month follow-up.

BACKGROUND: Perturbation-based balance training (PBT) has shown promising, although diverging, fall-preventive effects; however, the effects on important physical, cognitive and sociopsychological factors are currently unknown. The study aimed to evaluate these effects on PBT at three different time points (post-training, 6-months and 12-months) in community-dwelling older adults compared with regular treadmill walking. METHODS: This was a preplanned secondary analysis from a randomised, controlled trial performed in Aalborg, Denmark, between March 2021 and November 2022. Community-dwelling older adults aged ≥65 were randomly assigned to participate in four sessions (lasting 20 min each) of either PBT (intervention) or regular treadmill walking (control). All participants were assigned to four testing sessions: pretraining, post-training, 6-month follow-up and 12-month follow-up. At these sessions, physical, cognitive and sociopsychological measures were assessed. RESULTS: In total, 140 participants were randomly allocated to either the PBT or control group. Short-term (pretraining to post-training) between-group differences were seen for choice stepping reaction time (-49 ms, 95% CI -80 to -18), dual-task gait speed (0.05 m/s, 95% CI 0.01 to 0.09) favouring the PBT group. However, these improvements were not sustained at the 6-month and 12-month follow-up. No significant between-group differences were found in other physical, cognitive or sociopsychological factors. CONCLUSIONS: This study showed that PBT, in the short term, improved choice stepping reaction time and dual-task gait speed among community-dwelling older adults. Yet, these improvements were not retained for 6- or 12-months. The healthy state of the study's population may have imposed a ceiling effect limiting the ability to show any clinically relevant effects of PBT. TRIAL REGISTRATION NUMBER: NCT04733222.

Cognitive ability, education, height and body mass index in relation to risk of schizophrenia and mortality following its diagnosis.

This study examines the hypotheses that the traits of higher IQ, longer education and taller height are associated with lower risk of death as compared to traits of low IQ, short education, and short height in men with schizophrenia compared to men without schizophrenia. In total, 937,919 men born 1939-59 and 1983-1997 with information from conscription were followed for incident schizophrenia in Danish registries. Higher levels of cognitive ability, longer education, and taller height were associated with fewer cases of schizophrenia. In a sub-sample of 652,368 men with information on body mass index, underweight was associated with more and overweight and obesity were associated with fewer cases of schizophrenia compared with normal weight. Higher cognitive ability, longer education, and taller height were associated with fewer deaths from both natural and unnatural causes in both men with and without schizophrenia. Underweight was associated with more deaths from natural and unnatural causes, whereas overweight and obesity were associated with more deaths from natural causes and fewer deaths from unnatural causes in both groups of men. Due to interaction, tall height and long educational duration were associated with fewer deaths from natural causes, and obesity was associated with fewer deaths from unnatural causes among men with schizophrenia compared to men without. In conclusion, traits in young adulthood are associated with higher mortality in men with and without schizophrenia, but traits of long educational duration and obesity seem to be especially important for lower mortality in men with schizophrenia.

Amygdala and hippocampal substructure volumes and their association with improvement in mood symptoms in patients with mood disorders undergoing electroconvulsive therapy.

Electroconvulsive therapy (ECT) demonstrates favorable outcomes in the management of severe depressive disorders. ECT has been consistently associated with volumetric increases in the amygdala and hippocampus. However, the underlying mechanisms of these structural changes and their association to clinical improvement remains unclear. In this cross-sectional structural MRI study, we assessed the difference in amygdala subnuclei and hippocampus subfields in n = 37 patients with either unipolar or bipolar disorder immediately after eighth ECT sessions compared to (n = 40) demographically matched patients in partial remission who did not receive ECT (NoECT group). Relative to NoECT, the ECT group showed significantly larger bilateral amygdala volumes post-treatment, with the effect originating from the lateral, basal, and paralaminar nuclei and the left corticoamydaloid transition area. No significant group differences were observed for the hippocampal or cortical volumes. ECT was associated with a significant decrease in depressive symptoms. However, there were no significant correlations between amygdala subnuclei volumes and symptom improvement. Our study corroborates previous reports on increased amygdalae volumes following ECT and further identifies the subnuclei driving this effect. However, the therapeutic effect of ECT does not seem to be directly related to structural changes in the amygdala.

Characterization of gray matter volume changes from one week to 6 months after termination of electroconvulsive therapy in depressed patients.

BACKGROUND: Increased gray matter volume (GMV) following electroconvulsive therapy (ECT) has been well-documented, with limited studies reporting a subsequent decrease in GMV afterwards. OBJECTIVE: This study characterized the reversion pattern of GMV after ECT and its association with clinical depression outcome, using multi-site triple time-point data from the Global ECT-MRI Research Collaboration (GEMRIC). METHODS: 86 subjects from the GEMRIC database were included, and GMV in 84 regions-of-interest (ROI) was obtained from automatic segmentation of T1 MRI images at three timepoints: pre-ECT (T0), within one-week post-ECT (T1), and one to six months post-ECT (T2). RM-ANOVAs were used to assess longitudinal changes and LMM analyses explored associations between GMV changes and demographical and clinical characteristics. RESULTS: 63 of the 84 ROIs showed a significant increase-and-decrease pattern (RM-ANOVA, Bonferroni corrected p < 0.00059). Post hoc tests indicated a consistent pattern in each of these 63 ROIs: significant increase from T0 to T1inGMV, followed by significant decrease from T1 to T2 and no difference between T0 and T2, except for both amygdalae, right hippocampus and pars triangularis, which showed the same increase and decrease but GMV at T2 remained higher compared to T0. No consistent relationship was found between GMV change pattern and clinical status. CONCLUSION: The GEMRIC cohort confirmed a rapid increase of GMV after ECT followed by reversion of GMV one to six months thereafter. The lack of association between the GMV change pattern and depression outcome scores implies a transient neurobiological effect of ECT unrelated to clinical improvement.

Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Elevated Cathepsin S Serum Levels in New-Onset Type 1 Diabetes and Autoantibody-Positive Siblings.

Accumulating data suggest a role for the lysosomal protease cathepsin S (CTSS) in type 1 diabetes. Circulating CTSS is increased in type 1 diabetes; however, whether CTSS has protective or deleterious effects is unclear. The study's objectives were to examine the biomarker potential of CTSS in new-onset type 1 diabetes, and to investigate the expression and secretion of CTSS in human islets and ß-cells. The CTSS level was analyzed in serum from children with new-onset type 1 diabetes and autoantibody-positive and -negative siblings by ELISA. The expression and secretion of CTSS were evaluated in isolated human islets and EndoC-ßH5 cells by real-time qPCR, immunoblotting, and ELISA. The CTSS serum level was elevated in children with new-onset type 1 diabetes and positively associated with autoantibody status in healthy siblings. Human islets and EndoC-ßH5 cells demonstrated induction and secretion of CTSS after exposure to proinflammatory cytokines, a model system of islet inflammation. Analysis of publicly available single-cell RNA sequencing data on human islets showed that elevated CTSS expression was exclusive for the ß-cells in donors with type 1 diabetes as compared with nondiabetic donors. These findings suggest a potential of CTSS as a diagnostic biomarker in type 1 diabetes.

Rumination in patients with major depressive disorder before and after antidepressant treatment.

BACKGROUND: Rumination is a maladaptive response to distress characteristic of Major Depressive Disorder (MDD). It is unclear to what degree rumination is associated with depression severity prior to treatment and how it responds to antidepressant treatment. Therefore, we evaluated the association between rumination and depression severity in 92 untreated patients with MDD and explored the changes in rumination after initiation of antidepressant medication. METHOD: We measured rumination using the Rumination Response Scale (RRS) and depression severity with the Hamilton Depression Rating Scale (HDRS17 or HDRS6) before and after initiation of 12 weeks of antidepressant treatment. The association between RRS and pre-treatment HDRS17 was evaluated using a linear regression model. RRS at week 4, 8, and 12 across treatment response categories (remission vs. non-response) were evaluated using a mixed effect model. RESULTS: RRS was positively associated with depression severity prior to treatment at a trend level (p = 0.06). After initiation of treatment RRS decreased significantly (p < 0.0001) and remitters exhibited lower rumination compared to non-responders at week 4 (p = 0.03), 8 (p = 0.01), and 12 (p = 0.007). LIMITATIONS: The study had no placebo group. CONCLUSIONS: Although pre-treatment rumination did not significantly associate with depressive symptoms, rumination was closely connected to change in depressive symptoms. Tormented patients could be reassured that rumination symptoms may be alleviated over the course of antidepressant treatment.

Schema therapy versus treatment as usual for outpatients with difficult-to-treat depression: study protocol for a parallel group randomized clinical trial (DEPRE-ST).

BACKGROUND: About one third of patients with depression are in a condition that can be termed as "difficult-to-treat". Some evidence suggests that difficult-to-treat depression is associated with a higher frequency of childhood trauma and comorbid personality disorders or accentuated features. However, the condition is understudied, and the effects of psychotherapy for difficult-to-treat depression are currently uncertain. The aim of this trial is to investigate the beneficial and harmful effects of 30 sessions of individual schema therapy versus treatment as usual for difficult-to-treat depression in the Danish secondary, public mental health sector. METHODS: In this randomized, multi-centre, parallel-group, superiority clinical trial, 129 outpatients with difficult-to-treat depression will be randomized (1:1) to 30 sessions of individual schema therapy or treatment as usual; in this context mainly group-based, short-term cognitive behaviour or psychodynamic therapy. The primary outcome is the change from baseline in depressive symptoms 12 months after randomization, measured on the observer-rated 6-item Hamilton Rating Scale for Depression. The secondary outcomes are health-related quality of life assessed with the European Quality of Life 5 Dimensions 5 Level Version, functional impairment assessed with the Work and Social Adjustment Scale, psychological wellbeing assessed with the WHO-5 Well-being Index, and negative effects of treatment assessed with the Negative Effects Questionnaire. Exploratory outcomes are improvement on patient self-defined outcomes, personal recovery, anxiety symptoms, anger reactions, metacognitive beliefs about anger, and perseverative negative thinking. Outcomes will be assessed at 6, 12, and 24 months after randomization; the 12-month time-point being the primary time-point of interest. Outcome assessors performing the depression-rating, data managers, statisticians, the data safety and monitoring committee, and conclusion makers for the outcome article will be blinded to treatment allocation and results. To assess cost-effectiveness of the intervention, a health economic analysis will be performed. DISCUSSION: This trial will provide evidence on the beneficial and harmful effects, as well as the cost-effectiveness of schema therapy versus treatment as usual for outpatients with difficult-to-treat depression. The results can potentially improve treatment for a large and understudied patient group. TRIAL REGISTRATION: ClinicalTrials.gov NCT05833087. Registered on 15th April 2023 (approved without prompts for revision on 27th April 2023).

Oxidative Stress-Induced Damage to RNA and DNA and Mortality in Individuals with Psychiatric Illness.

Importance: All-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders. Objective: To study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality. Design, Setting, and Participants: This cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years. Exposures: History of psychiatric illness. Main Outcomes and Measures: Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level. Results: A total of 7728 individuals were included (3983 [51.5%] female; mean [SD] age, 58.6 [11.9] years), 3095 of whom (40.0%) had a history of psychiatric illness. Mean (SD) baseline 8-oxoGuo was statistically significantly higher in individuals with psychiatric illness than in those without (2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol; P < .001), whereas 8-oxodG was not. All-cause mortality was higher in the psychiatric illness group vs the no psychiatric illness group (hazard ratio [HR], 1.44; 95% CI, 1.27-1.64; P < .001) and increased sequentially with each increasing tertile of 8-oxoGuo excretion in both groups to an almost doubled risk in the psychiatric illness/high 8-oxoGuo group compared to the no psychiatric illness/low 8-oxoGuo reference group (HR, 1.99; 95% CI, 1.58-2.52; P < .001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex. Conclusions and Relevance: This study establishes systemic oxidative stress-induced damage to RNA as a potential mechanism in the accelerated aging observed in psychiatric disorders and urinary 8-oxoGuo as a potentially useful marker of mortality risk in individuals with psychiatric illness.

Effects of erythropoietin on cognitive impairment and prefrontal cortex activity across affective disorders: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. AIM: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. METHODS: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. RESULTS: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. CONCLUSIONS: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. TRIAL REGISTRATIONS: EudraCT no.: 2016-004023-24; ClinicalTrials.gov identifier: NCT03315897.

Sedative drug prescription patterns in Danish adults from 2002 through 2021. A register-based cohort study.

OBJECTIVE: Pharmacological treatment strategies for insomnia seem to vary, and there is lack of knowledge about how sedative drugs are used in a real-world setting. We investigated changes in sedative drug prescription patterns in Danish adults who initiated treatment between 2002 and 2016. METHODS: All adults with a first-time purchase of a sedative drug registered in the Danish National Prescription Register from 2002 through 2016 were followed for five years between 2002 and 2021 for subsequent prescriptions of sedative drugs, death, or emigration. Sedative drugs were classified into anxiolytic benzodiazepines (N05BA), hypnotic benzodiazepines (N05CD), Z-drugs (N05CF), melatonin (N05CH01), promethazine (R06AD), and low-dose quetiapine (N05AH04). Analyses were stratified on time: 2002-2006, 2007-2011, and 2012-2016. RESULTS: A total of 842,880 individuals purchased their first sedative drug between 2002 and 2016. Most of them (40.0%) initiated treatment between 2002 and 2006, whereas 29.2% initiated treatment in 2012-2016. In 2002-2006, anxiolytic benzodiazepines (46.4%), Z-drugs (42.8%), and hypnotic benzodiazepines (5.4%) were the most common first treatment. This pattern changed over time with a gradual increase in the use of melatonin, promethazine, and low-dose quetiapine, which in 2011-2016 accounted for 27% of all first treatments. During the five years from first prescription, around 27% shifted to a different sedative drug. This percentage increased slightly over time, but over time the first shift to another drug class was most often to a Z-drug or anxiolytic benzodiazepine. Few individuals (5.8%) had more than one shift and the third choice seemed randomly distributed across all other drug classes. CONCLUSION: Sedative drug prescriptions are distributed on different drug classes, with Z-drugs and anxiolytic benzodiazepines as the most frequent first treatment, and second choice in case of shift.

COMPASS: Double-ended saddle point search as a constrained optimization problem.

We present an algorithm to find first order saddle points on the potential energy surface (PES). The algorithm is formulated as a constrained optimization problem that involves two sets of atomic coordinates (images), a time-varying distance constraint and a constraint on the energy difference. Both images start in different valleys of the PES and are pulled toward each other by gradually reducing the distance. The search space is restricted to the pairs of configurations that share the same potential energy. By minimizing the energy while the distance shrinks, a minimum of the constrained search space is tracked. In simple cases, the two images are confined to their respective sides of the barrier until they finally converge near the saddle point. If one image accidentally crosses the barrier, the path is split at suitable locations and the algorithm is repeated recursively. The optimization is implemented as a combination of a quasi-Newton optimization and a linear constraint. The method was tested on a set of Lennard-Jones-38 cluster transitions and a set of 121 molecular reactions using density functional theory calculations. The efficiency in terms of energy and force evaluation is better than with competing methods as long as they do not switch to single-ended methods. The construction of a continuous search path with small steps and the ability to focus on arbitrary subsegments of the path provide an additional value in terms of robustness and flexibility.

The De Morton Mobility Index (DEMMI) in hospitalized geriatric patients is associated with risk of readmission, mortality, and discharge to a post-acute care facility: A nationwide register-based cohort study.

OBJECTIVE: To examine the association between the de Morton Mobility Index (DEMMI) score on admission in geriatric patients and readmission and mortality within 30, 180, and 365 days after discharge, and discharge to a post-acute care facility. METHODS: A nationwide register-based cohort study including 23,941 geriatric in-patients aged ≥65 years admitted to a geriatric ward between 2014 and 2017 and included in the Danish National Database for Geriatrics. The DEMMI score was categorized into four subcategories: very low mobility (DEMMI=0-24), low mobility (DEMMI=27-39), moderately reduced mobility (DEMMI=41-57), and independent mobility (DEMMI=62-100). Patients were followed 30, 180 and 365 days after discharge for readmission and mortality. Their risk of being discharged to a post-acute care facility was examined. Adjusted hazard ratios (HRs) and odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated. RESULTS: HRs for readmission within 30-days were 1.36 (1.24-1.48) for very low mobility, 1.30 (1.20-1.42) for low mobility and 1.17 (1.08-1.28) for moderately reduced compared with independent mobility. Similar results were seen for readmission within 180- and 365-days. For mortality, HR for 30-day mortality ranged from1.93 and 5.66, 180-day mortality between 1.62 and 3.19, and 365-day mortality between 1.54 and 2.81 compared with patients with independent mobility. OR for discharge to a post-acute care facility was 8.76 (7.29-10.53) for lowest compared with the highest DEMMI mobility subcategory. CONCLUSION: In geriatric in-patients, lower DEMMI scores on hospital admission are associated with increased rates of discharge to a post-acute care facility, and for readmission, and mortality within one year.

Exergaming Improves Cardiac Risk Factors in Prostate Cancer Patients: A Single-Blinded Randomized Controlled Trial.

Purpose: Androgen deprivation therapy (ADT) may induce unfavorable changes in metabolic outcomes, insulin sensitivity, insulin-like growth factors (IGFs), and in serum levels of adipocyte-derived hormones. In this preplanned randomized ancillary study, we aimed to investigate the ability of exercise to counteract alterations in triglyceride, cholesterol, waist circumference, and insulin caused by ADT in men with locally advanced and metastatic prostate cancer (PCa). Materials and Methods: Forty-six PCa patients undergoing treatment were randomized to 12 weeks of 180 minutes of weekly unsupervised home-based exergaming or usual care. Blood glucose, lipids, cholesterol, adiponectin, leptin, insulin sensitivity, and the insulin growth factor axis were measured at baseline, and after 12 and 24 weeks. Biomarkers were analyzed using a linear mixed-effect model of the difference between the groups from baseline to week 24. In addition, blood pressure, body mass index, body weight, and waist circumference were measured at baseline and after 12 weeks/end of intervention and analyzed using adjusted linear regression analysis. Results: After 24 weeks, a significant difference was seen between the intervention and usual care groups in plasma triglyceride (diff: 0.5 mmol/L, P = 0.02) and high-density lipoprotein (HDL; diff: 0.2 mmol/L, P = 0.01) favoring the intervention group, whereas IGF-binding protein-3 (diff: 148 µg/L, P = 0.01) favored the usual care group. The remaining outcomes were unaffected. Conclusion: Improvement in HDL cholesterol could be used as a primary biomarker in future randomized controlled trials investigating the cardiovascular protecting properties of exergaming.