Search results
Found 6357 matches for
The molecular circadian clock: From fundamental mechanisms to therapeutic promise in neurological disorders.
Circadian rhythms are intrinsic biological processes in all forms of life, governed by a molecular clock, organising physiological and behavioural cycles to align with a 24-hour light-dark cycle. The disruption of these rhythms has been linked to a plethora of neurological conditions and impacting cognitive and metabolic functions. This review offers a clear overview of the genetic and molecular mechanisms that govern the circadian clock. It focuses on the core clock feedback loops, the pathways involved and how these mechanisms are regulated. We explore how clocks in peripheral tissues are synchronised to the suprachiasmatic nucleus and how this is achieved through neuronal and humoral pathways. Additionally, we discuss how dysregulation in circadian rhythms contribute to neurological conditions and potential therapeutic treatments targeting circadian mechanisms. Understanding the mechanisms of circadian dysregulation provides insight into disease pathology and potential therapies. Interventions targeting circadian mechanisms, such as gene and drug delivery systems, show promise to restore rhythms and mitigate neurological symptoms. This review collates current knowledge on circadian biology and its applications addressing neurological dysfunctions, providing a foundation for potential chronotherapeutic interventions.
Neurodegenerative disease in C9orf72 repeat expansion carriers: population risk and effect of UNC13A.
The C9orf72 hexanucleotide repeat expansion (HRE) is the most common monogenetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative disease incidence in C9orf72 HRE carriers has been studied using cohorts from disease-affected families or by extrapolating from population disease incidence, potentially introducing bias. Age-specific cumulative incidence of ALS and dementia was estimated using Kaplan-Meier and competing risk models in C9orf72 HRE carriers compared to matched controls in UK Biobank. Risk modification by UNC13A genotype was examined. Of 490,331 individuals with valid genetic data, 701 had >100 repeats in C9orf72 (median age 55 [IQR 48-62], follow-up 13.4 years [12.3-14.1]). The cumulative incidence of ALS or dementia was 66% [95% CI 57-73%] by age 80 in C9orf72 HRE carriers versus 5.8% [4.5-7.0%] in controls, or 58% [50-64%] versus 5.1% [4.1-6.4%] accounting for the competing risk of other-cause mortality. Forty-one percent of dementia incidence accrued between age 75-80. C-allele homozygosity at rs12608932 in UNC13A increased ALS or dementia risk in C9orf72 HRE carriers (hazard ratio 1.81 [1.18 - 2.78]). C9orf72 HRE disease was incompletely penetrant in this population-based cohort, with risk modified by UNC13A genotype. This has implications for counselling at-risk individuals and modelling expected phenoconversion for prevention trials.
Sleep disruption and its psychological treatment in young people at risk of psychosis: A peer methods qualitative evaluation.
OBJECTIVES: A recent randomized controlled feasibility trial showed that sleep problems in young people at risk of psychosis can be successfully treated with psychological therapy and that this may bring additional benefits such as reducing depression, anxiety and paranoia. Here we report participants' qualitative experience of sleep problems and therapy. DESIGN: A peer-methods qualitative study employing reflexive thematic analysis. METHODS: Semi-structured interviews, co-facilitated by peer researchers, were conducted with 16 young patients at risk of psychosis and having sleep problems who participated in the SleepWell Trial (ISRCTN85601537). Ten interviewees had received the 12-week sleep therapy. RESULTS: Four themes were generated: (1) the challenge to access mental health treatment ('bouncing between services'), (2) sleep problems and mental health difficulties are intertwined ('an obvious link'), (3) flexibility in therapy provision matters ('tailored to me as a person') and (4) improving sleep leads to wider benefits ('fixing the sleep helped everything else'). Participants described a frustrating journey to access mental health treatment, marked by rejection and invalidation, which resulted in hopelessness and often resignation. The interaction between sleep disruption and other mental health difficulties was seen as obvious. Treatment for sleep problems was highly valued. The clear focus, therapeutic style and flexible delivery of the treatment was seen to create patient ownership, active engagement and hope. Participants described transformative changes: better sleep, fewer voices and fears and improved mood and confidence. Improving sleep made a difference to everyday life. CONCLUSIONS: Treating sleep problems in people at risk of psychosis is highly valued and often brings rapid and widespread improvements across a range of domains.
A 6-month supported online program for the treatment of persecutory delusions: Feeling Safer.
BACKGROUND: Based on an efficacious face-to-face theory-driven psychological therapy for persecutory delusions in the context of psychosis, we set out to develop a scalable guided 6-month online program. The aim was an intervention that patients can easily access and use, produces large clinical effects, and can be supported by a range of mental health professionals in less contact time than face-to-face therapy. We report here the proof-of-concept testing. At least moderate-sized clinical effects were required to progress to a randomized controlled trial (RCT). METHODS: In the 6-month Feeling Safer online program, a certified medical device, patients complete a brief assessment and then are provided with up to 10 modules that match their difficulties. Regular remote meetings with a mental health professional also take place. These may be supplemented by in-person visits. A pre- to post-treatment cohort trial was conducted with 14 patients with persistent persecutory delusions. The primary outcome was the Psychotic Symptoms Rating Scale (PSYRATS)-Delusions. RESULTS: Satisfaction and usability ratings of the program were high. Very large reductions in persecutory delusions were observed (PSYRATS mean reduction = 7.1, 95% C.I. = 3.4, 10.8, n = 13, Cohen's d = 3.0). There were large improvements in paranoia, anxiety, depression, agoraphobic distress, psychological wellbeing, meaningful activity, personal recovery, recovering quality of life, and moderate improvements in insomnia, agoraphobic avoidance, and quality of life. CONCLUSIONS: The clinical effects associated with Feeling Safer were very high, comparable to those seen in the evaluations of the face-to-face therapy, and enable progression to an RCT.
Dose-dependent and tissue-specific adverse effects of exogenous glucocorticoids: insights for optimizing clinical practice.
PURPOSE: There is limited data on dose-specific metabolic effects of exogenous glucocorticoids (GC) doses. This study aimed to investigate the differential tissue-specific and dose-dependent effects of low-to-intermediate prednisolone doses on insulin sensitivity and bone metabolism in healthy individuals. METHODS: We performed a post-hoc pooled analysis of three independent clinical trials, each administering one week of daily prednisolone at 10 mg, 15 mg, or 20 mg, in a total of 30 different healthy male volunteers (aged 18-65; BMI 20-35 kg/m²; normal kidney function). Outcome measures included: changes in liver (endogenous glucose production-EGP, β-hydroxybutyrate-OHB), muscle (M/I value, Glucose disposal-Gd) and adipose tissue (NEFA, glycerol) insulin sensitivity assessed across a hyperinsulinemic-euglycemic clamp. Bone turnover was evaluated through osteocalcin levels. RESULTS: Prednisolone 10 mg had minimal impact on metabolic parameters. 15 mg and 20 mg caused similar reductions (no dose effects) in liver (time effect p
Lower risk of dementia with AS01-adjuvanted vaccination against shingles and respiratory syncytial virus infections.
AS01-adjuvanted shingles (herpes zoster) vaccination is associated with a lower risk of dementia, but the underlying mechanisms are unclear. In propensity-score matched cohort studies with 436,788 individuals, both the AS01-adjuvanted shingles and respiratory syncytial virus (RSV) vaccines, individually or combined, were associated with reduced 18-month risk of dementia. No difference was observed between the two AS01-adjuvanted vaccines, suggesting that the AS01 adjuvant itself plays a direct role in lowering dementia risk.
Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart muscle disorder. Although the biophysical mechanisms by which gene variants in sarcomeric proteins disrupt cardiomyocyte function are largely understood, the cellular and molecular pathways leading to the complex, variable, and adverse remodeling of the non-myocyte compartment are unexplained. Here, we report that postmortem and explanted human HCM hearts exhibited chronic focal leukocyte infiltration and prominent activation of immune cells. Gene set enrichment analysis (GSEA) revealed that active immune responses were present in the mid- and late-stage HCM human hearts and in mouse hearts from several HCM mouse models. The alpha cardiac actin 1-E99K (Actc1E99K) HCM mouse model was selected for the study because it closely recapitulates the features of progressive remodeling and fibrosis seen in advanced disease in patients. Genetic depletion of lymphocytes in recombination activating gene 1-knockout (Rag-1KO) mice led to marked exacerbation of adverse cardiac remodeling in the Actc1E99K mice. Detailed characterization of cardiac regulatory T cells (Treg cells) demonstrated a time-dependent increase in Actc1E99K hearts with altered immunosuppressive profiles. Adoptive transfer of splenic Treg cells reduced cardiac fibrosis and improved systolic dysfunction in Actc1E99K mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti-IL-2 complex (IL-2/c), which specifically induced Treg cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in Actc1E99K mice. These data contribute to our understanding of HCM and support the use of Treg cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.
Aficamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: 48-Week Results From FOREST-HCM.
BACKGROUND: Long-term safety and efficacy data for aficamten in symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES: This study aims to evaluate 48-week experience from the ongoing FOREST-HCM (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy) study. METHODS: Obstructive hypertrophic cardiomyopathy participants in an aficamten study (REDWOOD-HCM [Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM; NCT04219826]; SEQUOIA-HCM [Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT05186818]) could enroll in this phase 2/3, open-label, extension study. Participants received aficamten 5 mg once daily titrated ≤20 mg based on site-read echocardiographic assessments of Valsalva left ventricular outflow tract gradient and left ventricular ejection fraction. RESULTS: From May 2021 to October 2023, 213 participants enrolled; 46 participants with 48 weeks of follow-up were evaluated (mean age: 59.7 years; female: n = 26 [56.5%]). There were rapid, substantial, and sustained reductions in mean resting (-40 ± 34 mm Hg) and Valsalva peak left ventricular outflow tract gradient (-53 ± 39 mm Hg) from baseline to week 48. A total of 82% experienced ≥1 NYHA functional class improvement; 31% experienced a 20-point improvement in Kansas City Cardiomyopathy Questionnaire-Clinical Summary score. There were substantial reductions (mean change) in maximum left ventricular wall thickness (-1.2 ± 1.6 mm; P < 0.0001), left atrial volume index (-3.5 ± 6.6 mL/m2; P = 0.0008), lateral E/e' (-2.2 ± 6.1; P = 0.02), and cardiac biomarkers (P ≤ 0.0031). Aficamten was well tolerated with 2 (4.3%) asymptomatic and transient instances of left ventricular ejection fraction <50% (range: 47%-49%), neither resulting in drug discontinuation, and no new-onset atrial fibrillation. CONCLUSIONS: Aficamten treatment over 48 weeks was well tolerated and associated with substantial and durable relief of obstruction and symptom burden, lower cardiac biomarker levels, and cardiac phenotypic changes, which may indicate favorable cardiac remodeling. (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506).
Quantification of Optical Coherence Tomography Features in >3500 Patients with Inherited Retinal Disease Reveals Novel Genotype-Phenotype Associations.
PURPOSE: To quantify spectral-domain optical coherence tomography (SD-OCT) images cross-sectionally and longitudinally in a large cohort of molecularly characterized patients with inherited retinal disease (IRDs) from the UK. DESIGN: Retrospective study of imaging data. PARTICIPANTS: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone macular SD-OCT imaging at Moorfields Eye Hospital (MEH) between 2011 and 2019. We retrospectively identified 4,240 IRD patients from the MEH database (198 distinct IRD genes), including 69,664 SD-OCT macular volumes. METHODS: Eight features of interest were defined: retina, fovea, intraretinal cystic spaces (ICS), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), pigment epithelium detachment (PED), ellipsoid zone loss (EZ-loss) and retinal pigment epithelium loss (RPE-loss). Manual annotations of five b-scans per SD-OCT volume was performed for the retinal features by four graders based on a defined grading protocol. A total of 1,749 b-scans from 360 SD-OCT volumes across 275 patients were annotated for the eight retinal features for training and testing of a neural-network-based segmentation model, AIRDetect-OCT, which was then applied to the entire imaging dataset. MAIN OUTCOME MEASURES: Performance of AIRDetect-OCT, comparing to inter-grader agreement was evaluated using Dice score on a held-out dataset. Feature prevalence, volume and area were analysed cross-sectionally and longitudinally. RESULTS: The inter-grader Dice score for manual segmentation was ≥90% for retina, ICS, SRF, SHRM and PED, >77% for both EZ-loss and RPE-loss. Model-grader agreement was >80% for segmentation of retina, ICS, SRF, SHRM, and PED, and >68% for both EZ-loss and RPE-loss. Automatic segmentation was applied to 272,168 b-scans across 7,405 SD-OCT volumes from 3,534 patients encompassing 176 unique genes. Accounting for age, male patients exhibited significantly more EZ-loss (19.6mm 2 vs 17.9mm 2 , p<2.8×10 -4 ) and RPE-loss (7.79mm 2 vs 6.15mm 2 , p<3.2×10 -6 ) than females. RPE-loss was significantly higher in Asian patients than other ethnicities (9.37mm 2 vs 7.29mm 2 , p<0.03). ICS average total volume was largest in RS1 (0.47mm 3 ) and NR2E3 (0.25mm 3 ), SRF in BEST1 (0.21mm 3 ) and PED in EFEMP1 (0.34mm 3 ). BEST1 and PROM1 showed significantly different patterns of EZ-loss (p<10 -4 ) and RPE-loss (p<0.02) comparing the dominant to the recessive forms. Sectoral analysis revealed significantly increased EZ-loss in the inferior quadrant compared to superior quadrant for RHO (Δ=-0.414 mm 2 , p=0.036) and EYS (Δ=-0.908 mm 2 , p=1.5×10 -4 ). In ABCA4 retinopathy, more severe genotypes (group A) were associated with faster progression of EZ-loss (2.80±0.62 mm 2 /yr), whilst the p.(Gly1961Glu) variant (group D) was associated with slower progression (0.56 ±0.18 mm 2 /yr). There were also sex differences within groups with males in group A experiencing significantly faster rates of progression of RPE-loss (2.48 ±1.40 mm 2 /yr vs 0.87 ±0.62 mm 2 /yr, p=0.047), but lower rates in groups B, C, and D. CONCLUSIONS: AIRDetect-OCT, a novel deep learning algorithm, enables large-scale OCT feature quantification in IRD patients uncovering cross-sectional and longitudinal phenotype correlations with demographic and genotypic parameters.
Gamma activation spread reflects disease activity in amyotrophic lateral sclerosis.
OBJECTIVE: A non-invasive measure of cerebral motor system dysfunction would be valuable as a biomarker in amyotrophic lateral sclerosis (ALS). Task-based magnetoencephalography (tMEG) measures the magnetic fields generated by cortical neuronal oscillatory activity during task performance. Gamma activations are periods of high-power and high-frequency cortical oscillations integral to motor control. METHODS: tMEG was undertaken during 60 bilateral isometric hand grip exercises in ALS (n = 42) and compared with healthy controls (HC, n = 33). Gamma activation spread (GAS) was estimated by calculating the number of activated regions during each 100 ms time-bin and compared statistically between groups. Gamma activation patterns were visualised by plotting each participant's brain activity separately as a 2-dimensional video. RESULTS: There was no difference in grip strength between groups. GAS was greatly increased in the ALS group compared to HC (p
Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus.
The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn coordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing to map the genomic localization of ZFHX3-binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites, co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12 h light-12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.
Performance Evaluation of Algorithms to Estimate Daily Sedentary Time Using Wrist-Worn Sensors in Free-Living Adults
Purpose: Given the limited real-world testing of algorithms for wrist-worn sensors to estimate sedentary time, we examined the performance of 21 algorithms in free-living adults. Methods: Seventy-one adults (35–65 years) wore a GENEActiv (wrist) and an activPAL (thigh) sensor for up to 10 days. activPAL was our reference measure. We estimated sedentary time (hours/day) using 21 classification algorithms, including cut-point and machine-learning methods. Valid days from each monitor were matched by date and mean values were calculated. Equivalence testing (±10%) and linear regression were used to compare each algorithm’s estimate to the reference, over all participants and by sex and age. Results: activPAL recorded a mean of 9.4 hr/day sedentary. Five of 21 algorithms (24%) estimated sedentary time within 10% (±0.94 hr) of the reference. Two of these methods employed machine-learning algorithms (Trost Extended, OxWearables) and three employed cut-points (GGIR Euclidean norm minus one [ENMO] 40 mg; Bakrania ENMO 32.6 mg; Fraysse ENMOa 62.5 mg). Variance explained in linear regression was relatively high for the machine-learning (R2 = .44–.63) and cut-point algorithms developed for younger (R2 = .30–.64) and older (R2 = .45–.66) adults. More accurate performance was noted for algorithms developed in studies using posture-based ground truth measures and conducted in free-living settings. Conclusion: Fifteen of 21 (71%) algorithms produced estimates of sedentary time that were moderate-strongly correlated with the reference measure, but only five (24%) were within 10% of the reference. Free-living benchmarking studies like this can identify more accurate and precise algorithms to estimate sedentary time and identify characteristics of algorithm development studies that yield better results.
Non-mental health inpatient and emergency care hospital costs associated with four mental disorders in Europe: a modelling study.
BackgroundThe prevalence of physical health conditions is higher among people with mental disorders than the general population, and these conditions have subsequent excess costs. Estimating the magnitude of these excess costs would support better integrated mental and physical health care. The aim of this study was to estimate the excess annual hospital costs of non-mental health related inpatient and emergency care utilisation for four mental disorders in 32 European countries.MethodsIn this modelling study, we obtained data on the working-age population (aged 20-64 years) of 32 European countries from the European Statistical Agency, the 2019 Global Burden of Disease, Injuries, and Risk Factors Study, epidemiological and cost evidence syntheses, and listed country-specific estimates. We estimated the non-mental health inpatient costs and emergency care hospital costs associated with the excess physical health burden of alcohol use disorders, bipolar disorder, depressive disorders, and schizophrenia in purchasing power standard Euros (PPS€) for 2019. Total physical comorbidity hospital costs were calculated by summing attributable non-mental health inpatient and emergency hospital costs across all physical health diagnoses by ICD-10 category for each mental disorder in all countries. Excess costs represent the proportion of total costs that were attributable to the excess physical health burden. People with lived experiences informed the original project plans.FindingsIn 2019, there were 312·5 million people of working age across 32 European countries. Total annual non-mental health inpatient and emergency care hospital costs were PPS€20·3 billion for alcohol use disorders, PPS€6·7 billion for bipolar disorder, PPS€26·5 billion for depressive disorders, and PPS€1·8 billion for schizophrenia, with considerable variation observed among countries. The proportion of excess costs were 59·4% (PPS€12·1 billion) for alcohol use disorder, 56·7% (PPS€3·8 billion) for bipolar disorder, 52·7% (PPS€14·0 billion) for depressive disorders, and 35·6% (PPS€0·7 billion) for schizophrenia.InterpretationThese first comprehensive European estimates indicate that non-mental health inpatient and emergency care hospital costs contributed substantially to the total costs associated with four mental disorders. The excess costs equated to 1·8% of the included countries' overall health-care expenditure and 0·16% of their gross domestic products. Estimates are conservative because they are limited to diagnosed mental disorders prevalent among working-age adults. A 1·0% reduction in the excess physical health burden of these mental disorders could lead to annual savings of more than PPS€190 million in non-mental health hospital costs in Europe.FundingEuropean College of Neuropsychopharmacology.
A single dose of lamotrigine induces a positive memory bias in healthy volunteers.
BACKGROUND: Lamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks in healthy volunteers, previously shown to be sensitive to antidepressant drug action in similar experimental designs. METHODS: Healthy volunteers (n = 36) were randomized in a double-blind design to receive a single dose of placebo or 300 mg lamotrigine. Mood and subjective effects were monitored throughout the study period, and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post-administration. RESULTS: Participants receiving lamotrigine showed increased accurate recall of positive versus negative self-descriptors, compared to those in the placebo group. There were no other significant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience. CONCLUSIONS: Lamotrigine did not induce widespread changes in emotional processing. However, there was increased positive bias in emotional memory, similar to the effects of antidepressants reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.
Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder.
Background: The largest randomized study of psilocybin to date demonstrated the efficacy of COMP360 25 mg (Compass Pathways' investigational proprietary pharmaceutical-grade synthesized psilocybin formulation) in participants with treatment-resistant depression (COMP 001), compared with 10 mg and 1 mg doses. Here, we report findings from COMP 004, a 52-week observational follow-up of patients from COMP 001 and COMP 003, a small open-label study of the coadministration of 25 mg COMP360 with continuing antidepressant treatment. Methods: Adverse events (AEs) were collected over the full 52-week period. The primary efficacy endpoint was time to a prespecified depressive event over the 52 weeks following COMP360 administration in COMP 001 participants, presented as Kaplan-Meier estimates. A post hoc analysis included only participants that entered COMP 004. Data were collected from July 2020 to July 2022. Results: Sixty-six participants entered COMP 004 (COMP 001, n = 58 [25 mg group n = 22, 10 mg group n = 19, 1 mg group n = 17]; COMP 003, n = 8). Few AEs were reported post-entry into COMP 004, with 1 AE of mild suicidal ideation in the 1 mg group deemed possibly related to study drug. For all COMP 001 patients (n = 233), median time to depressive event was greater for the 25 mg group (92 days) compared to the 10 mg (83 days) and 1 mg (62 days) groups, with the majority of participants having had a depressive event by Week 12 (25 mg n = 37/75, 10 mg n = 38/79, 1 mg n = 44/75). The post hoc supplementary analysis of those who enrolled in COMP 004 from COMP 001 exhibited the difference between groups more strikingly (25 mg, 189 days; 10 mg, 43 days; 1 mg, 21 days); however, only 10 participants experienced a depressive event post-COMP 004 enrollment (25 mg n = 6, 10 mg n = 3, 1 mg n = 1) from COMP 001 and none from COMP 003. At COMP 004 entry, the 1 mg group had the highest number of participants on antidepressant medication (n = 10; 10 mg, n = 9; 25 mg, n = 6) and generally initiated treatment earlier. Conclusion: Over 52 weeks, a single administration of 25 mg psilocybin suggested longer maintenance of antidepressant effect than both 1 mg and 10 mg. Larger long-term studies are required to confirm these findings and provide clarity on the longer-term effects of psilocybin. Trial Registration: ClinicalTrials.gov identifier: NCT04519957.
Circadian rhythms in metabolism and mental health: a reciprocal regulatory network with implications for metabolic and neuropsychiatric disorders
Circadian rhythms orchestrate metabolism and brain function, aligning internal physiological processes with the 24-hour day–night cycle. Growing evidence highlights a reciprocal relationship between circadian regulation, metabolism, and neurobiological processes. Circadian disruption impairs glucose and lipid homeostasis, alters neurotransmitter and endocrine signalling, and triggers stress response, forming a feedback loop that impacts metabolism and brain function. These disturbances are implicated in many conditions, such as obesity, diabetes, depression, and bipolar disorder. This review examines recent advances in the interplay between circadian regulation, metabolism, and mental health, emphasising shared molecular mechanisms and their role in disease progression. Understanding these connections may ultimately inform therapeutic strategies that integrate circadian-based approaches to improve treatments for metabolic and psychiatric disorders.
Learning How to Improve the Treatment of Persecutory Delusions: Using a Principal Trajectories Analysis to Examine Differential Effects of Two Psychological Interventions (Feeling Safe, Befriending) in Distinct Groups of Patients.
BACKGROUND: A theory-driven cognitive therapy (Feeling Safe) has produced much better outcomes for patients with persecutory delusions. There are four distinct response classes: very high delusion conviction with large improvement, very high delusion conviction with no response, high delusion conviction with large improvement, and high delusion conviction with modest improvement. Our objective was to apply principal trajectories analysis, a novel statistical method, to original trial data to estimate whether these groups may have responded differently to a different intervention: befriending. DESIGN: One hundred and thirty patients with persistent persecutory delusions were randomised to six months of Feeling Safe or befriending. Baseline assessments were used to assign patients allocated to befriending (who did not receive Feeling Safe) into the four Feeling Safe response classes. The treatment effect, including on potential mediators, was then estimated for these classes. RESULTS: Patients in two treatment response classes (Very high conviction/large improvement, High conviction/large improvement) benefited more from Feeling Safe, patients in one group (Very high conviction/no improvement) benefited more from befriending, and patients in the remaining group (High conviction/moderate improvement) benefited equally from the interventions. Mechanism differences were detected when Feeling Safe was superior to befriending, but not when befriending was superior. CONCLUSIONS: There may be patients with psychosis who benefit more from one type of therapy than another, likely due to different change mechanisms. The application of principal trajectories has generated testable hypotheses and a potential step toward personalised treatment. We recommend an investigation of whether sequential provision of the treatment types could enhance patient outcomes. Keywords: persecutory, delusions, outcome trajectories, psychosis, cognitive therapy.
Retinal microvascular phenotypes can track small vessel disease burden and CPAP treatment effectiveness in obstructive sleep apnea.
Optical coherence tomography angiography (OCT-A) retinal imaging enables in vivo visualization of the retinal microvasculature that is developmentally related to the brain and can offer insight on cerebrovascular health. We investigated retinal phenotypes and neuroimaging markers of small vessel disease (SVD) in individuals with obstructive sleep apnoea (OSA). We enrolled 44 participants (mean age 50.1 ± SD 9.1 years) and performed OCT-A imaging before and after continuous positive airway pressure (CPAP) therapy. Pre-treatment analyses using a generalized estimating equations model adjusted for relevant covariates, revealed perivascular spaces (PVS) volume in basal ganglia associated with greater foveal vessel density (fVD) (p-value
Sleep-disordered breathing in children and adults with intellectual disability: mind the gap!
BackgroundIn adults and children with intellectual disability (ID), sleep -disordered breathing (SDB) is thought to be common. However, large epidemiological studies are lacking, and there are few studies on optimal methods of investigation and even fewer randomised, controlled intervention trials of treatment.MethodPeer-reviewed publications from various databases were examined in line with search terms relevant to ID and SDB spanning the years 200-2024.ResultsFindings suggest that, due to comorbid conditions, children and adults with ID may experience both an increased risk of SDB, as well as lower frequency of diagnosis. SDB can compromise the emotional, physical and mental health of individuals with ID. Appropriate treatment when tolerated leads to an improvement in health and well-being and several studies emphasized the importance of consistent follow-up of people with ID - something that is not universally occurring during childhood, in the transition to adulthood and during adulthood itself. As the most frequently occurring form of ID worldwide, we use Down syndrome as a specific example of how diagnosing and treating SDB can lead to improved outcomes.ConclusionsThis review highlights the importance of identifying SDB in this heterogenous population, recognising the multi-faceted, deleterious consequences of untreated SDB in people with ID, and presents some strategies that can be harnessed to improve diagnosis and management. Until further ID-specific research is available, we urge flexibility in the approach to people with ID and SDB based in guidelines and standard practice developed for the typically developing population.