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Results from an insight review commissioned by the Wellcome Trust, highlights what is currently known about the benefits and risks of using selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression and anxiety in young people.
Antidepressant Switching as a Proxy Phenotype for Drug Nonresponse: Investigating Clinical, Demographic, and Genetic Characteristics.
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacological therapy in major depressive disorder (MDD), but treatment response rates are low. Clinical trials lack the power to study the genetic contribution to SSRI response. Real-world evidence from electronic health records provides larger sample sizes, but novel response definitions are needed to accurately define SSRI nonresponders. METHODS: In the UK Biobank (UKB) (N = 38,813) and Generation Scotland (N = 1777) datasets, SSRI switching was defined using ≤90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Nonswitchers were participants with ≥3 consecutive prescriptions for an SSRI. In the UKB, clinical, demographic, and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated. RESULTS: In the UKB, 5133 (13.2%) SSRI switchers and 33,680 nonswitchers were defined. The mean time to switch was 28 days (interquartile range, 17-49). Switching patterns were consistent across the UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (odds ratio [OR] [95% CI] for a university degree, 0.73 [0.67-0.79] compared with no qualifications) were associated with lower levels of switching. PGSs for nonremission, based on clinical studies, were associated with increased risk of switching (OR, 1.07 [1.02-1.12], p = .007). MDD PGSs and family history of depression were not significantly associated with switching. Using genome-wide complex trait Bayesian, the single nucleotide polymorphism-based heritability was approximately 4% (SE 0.016) on the observed scale. CONCLUSIONS: This study identified SSRI switching as a proxy for nonresponse, scalable across biobanks with electronic health records, capturing demographics and genetics of treatment nonresponse, and independent of MDD genetics.
Cannabis Withdrawal and Psychiatric Intensive Care
ImportanceCannabis use is common in people with severe mental illness and its adverse effects on outcomes are well established. However, adverse outcomes may also result from cannabis withdrawal syndrome (CWS). CWS includes symptoms such as agitation, irritability, and aggression, and typically peaks after 3 to 5 days of abstinence.ObjectiveTo assess whether cannabis use prior to admission is associated with an increase in the risk of transfer to a psychiatric intensive care unit (PICU) during the cannabis withdrawal risk period.Design, Setting, and ParticipantsThis retrospective cohort study used clinical data from a secondary mental health care database and took place at 4 psychiatric hospitals in London, United Kingdom, between January 2008 and December 2023. Patients included adults admitted to general psychiatric wards and PICUs. Data were analyzed from June 2023 to February 2025.ExposureCannabis use was determined from clinical records, using natural language processing and manual review.Main Outcomes and MeasuresThe primary outcome was transfer from a general ward to PICU during the cannabis withdrawal risk period (3 to 5 days after presentation to the hospital). Secondary outcomes included admission to PICU at any time point. Outcomes were analyzed according to cannabis use status with multivariable models, which adjusted for age, gender, ethnicity, diagnosis, tobacco use, stimulant use, comorbid alcohol or substance use disorder, and admission year.ResultsThere were 52 088 hospital admissions identified, of which 4691 involved admission to a PICU (9.0%). Cannabis users were more likely to be admitted to a PICU than nonusers (adjusted odds ratio [aOR], 1.44; 95% CI, 1.33-1.55; P < .001). There were 1236 admissions where the patient was transferred to PICU after initial admission to a general ward (mean [SD] age, 33.4 [10.4] years; 810 male [66%] and 426 female [34%]). At 3 to 5 days postpresentation (the risk period for cannabis withdrawal), transfer from a general ward to a PICU was more common in cannabis users (31.0%) than nonusers (24.2%) (aOR, 1.36; 95% CI, 1.01-1.81; P = .04). The association was particularly evident in women (aOR, 2.03; 95% CI, 1.22-3.39; P = .007) and in those older than 35 years (aOR, 2.53; 95%CI: 1.52-4.21; P < .001).Conclusions and RelevancePeople with severe mental illness who are cannabis users may develop cannabis withdrawal syndrome shortly after hospital admission, and this can exacerbate their mental state.
The effect of D-cycloserine on brain connectivity over a course of pulmonary rehabilitation - A randomised control trial with neuroimaging endpoints.
Combining traditional therapies such as pulmonary rehabilitation with brain-targeted drugs may offer new therapeutic opportunities for the treatment of chronic breathlessness. Recently, we asked whether D-cycloserine, a partial NMDA-receptor agonist which may enhance behavioural therapies, modifies the relationship between breathlessness related brain activity and breathlessness anxiety over pulmonary rehabilitation. However, whether any changes are supported by alterations to underlying brain structure remains unknown. Here we examine the effect of D-cycloserine over a course of pulmonary rehabilitation on the connectivity between key brain regions associated with the processing of breathlessness anxiety. 72 participants with mild-to-moderate COPD took part in a longitudinal study in parallel to their pulmonary rehabilitation course. Diffusion tensor brain imaging and clinical measures of respiratory function were collected at three time points (before, during and after pulmonary rehabilitation). Participants were assigned to 250mg of D-cycloserine or placebo, which they were administered with on four occasions in a randomised, double-blind procedure. Following the first four sessions of pulmonary rehabilitation (visit 2), during which D-cycloserine was administered, improvements in breathlessness anxiety were linked with increased insula-hippocampal structural connectivity in the D-cycloserine group when compared to the placebo group. No differences were found between the two groups following the completion of the full pulmonary rehabilitation course 4-6 weeks later (visit 3). The action of D-cycloserine on brain connectivity appears to be restricted to within a short time-window of its administration. This temporary boost of the brain connectivity of two key regions associated with the evaluation of how unpleasant an experience is may support the re-evaluation of breathlessness cues, illustrated improvements in breathlessness anxiety. Trial registration ClinicalTrials.gov (NCT01985750).
Collaborative risk assessment and management planning in secure mental health services in England: protocol for a realist review.
INTRODUCTION: Secure mental health pathways are complex. They are typically based around secure hospitals, but also interface with justice agencies and other clinical services, including in the community. Consideration of risk is fundamental to clinical care and to decisions relating to a patient's stepwise journey through the pathway. Patient autonomy and involvement in decision-making are policy priorities for health services. However, improving collaboration in risk-related decisions in secure services is complicated by potential issues with insight and capacity and the necessary involvement of other agencies. In addition, although some collaborative approaches are feasible and effective, their impact, mechanisms and the contexts in which they work are not well understood. Therefore, using realist methodology, this review will outline what works, for whom, why and under what circumstances in terms of collaborative risk assessment and management in secure services. METHODS AND ANALYSIS: The review will consist of four stages: (1) Development of an initial programme theory to explain how and why collaborative risk assessment and management works for different groups of people, (2) search for evidence, (3) data selection and extraction and (4) evidence synthesis and development of a final programme theory. Our initial programme theory will be informed by an informal search of the literature and consultation with experts and patient and public involvement and engagement representatives. Following this, our formal literature search will include both the published and unpublished literature. During full text screening, each document will be assessed according to the principles of rigour and relevance and, if included, data will be extracted and synthesised to refine the programme theory. ETHICS AND DISSEMINATION: This protocol is for a review of published literature and so does not require ethical approval. The main output will be the final programme theory. Remaining gaps will inform planned future work to further refine the theory using mixed methods. Our dissemination strategy will be codeveloped with our public and patient involvement group and will include publishing findings in a peer-reviewed journal and presenting findings at relevant professional conferences, as well as engaging patient, carer and clinician groups directly.
Working Memory Predicts Long-Term Recognition of Auditory Sequences: Dissociation Between Confirmed Predictions and Prediction Errors.
Memory is a crucial cognitive process involving several subsystems: sensory memory (SM), short-term memory (STM), working memory (WM), and long-term memory (LTM). While each has been extensively studied, the interaction between subsystems, particularly in relation to predicting temporal sequences, remains largely unexplored. This study investigates the association between WM and LTM, and how these relate to aging and musical training. Using three datasets with a total of 243 healthy volunteers across various age groups, we examined the impact of WM, age, and musical training on LTM recognition of novel and previously memorized musical sequences. Our results show that WM abilities are positively associated with the identification of novel sequences, but not with the recognition of memorized sequences. Additionally, musical training has a similar positive impact on the identification of novel sequences, while increasing age is associated with reduced memory performance. Different cognitive processes are involved in handling prediction errors compared to confirmatory predictions, and WM contributes to these processes differently. Future research should extend our investigation to populations with memory impairments and explore the underlying neural substrates.
Introduction of point-of-care blood testing in early intervention in psychosis services: effects on physical health screening.
BACKGROUND: There is a significant mortality gap between the general population and people with psychosis. Completion rates of regular physical health assessments for cardiovascular risk in this group are suboptimal. Point-of-care testing (POCT) for diabetes and hyperlipidaemia - providing an immediate result from a finger-prick - could improve these rates. AIMS: To evaluate the impact on patient-clinician encounters and on physical health check completion rates of implementing POCT for cardiovascular risk markers in early intervention in psychosis (EIP) services in South East England. METHOD: A mixed-methods, real-world evaluation study was performed, with 40 POCT machines introduced across EIP teams in all eight mental health trusts in South East England from March to May 2021. Clinician training and support was provided. Numbers of completed physical health checks, HbA1c and lipid panel blood tests completed 6 and 12 months before and 6 months after introduction of POCT were collected for individual patients. Data were compared with those from the South West region, which acted as a control. Clinician questionnaires were administered at 2 and 8 months, capturing device usability and impacts on patient interactions. RESULTS: Post-POCT, South East England saw significant increases in HbA1c testing (odds ratio 2.02, 95% CI 1.17-3.49), lipid testing (odds ratio 2.38, 95% CI 1.43-3.97) and total completed health checks (odds ratio 3.61, 95% CI 1.94-7.94). These increases were not seen in the South West. Questionnaires revealed improved patient engagement, clinician empowerment and patients' preference for POCT over traditional blood tests. CONCLUSIONS: POCT is associated with improvements in the completion and quality of physical health checks, and thus could be a tool to enhance holistic care for individuals with psychosis.
The therapeutic potential of exercise in post-traumatic stress disorder and its underlying mechanisms: A living systematic review of human and non-human studies
Background Exercise for post-traumatic stress disorder (PTSD) is a potentially effective adjunct to psychotherapy. However, the biopsychosocial mechanisms of exercise are not well understood. This co-produced living systematic review synthesizes evidence from human and non-human studies. Methods We Included controlled human and non-human studies involving searches of multiple electronic databases (until 31.10.23). Records were screened, extracted, assessed for risk of bias, and reconciled by two independent reviewers. The primary outcome for human studies was PTSD symptom severity, while outcomes of interest for non-human studies included freezing behaviour, fear memory, fear generalization, startle response, and locomotion. Data were synthesised with random-effects meta-analysis. Results Eleven human studies and 14 non-human studies met the eligibility criteria. Results of human studies showed that exercise was not associated with symptom severity improvement compared to control (standardized mean difference [SMD] -0.08, 95% confidence interval [CI] -0.24 to 0.07). High-intensity exercise reduced PTSD symptoms scores more than moderate-intensity exercise. There was insufficient data to examine the effects of exercise on functional impairment, PTSD symptom clusters, and PTSD remission. Only three studies, all at high risk of bias, examined mechanisms of exercise with inconclusive results. Results of non-human studies showed that exercise was associated with improvement in all behavioural outcomes, including locomotor activity (SMD 1.30, 95% CI 0.74 to 1.87, 14 studies), and changes in several neurobiological markers, including increase in brain-derived neurotrophic factor (SMD 1.79, 95% CI 0.56 to 3.01). Conclusions While non-human studies provide compelling evidence for the beneficial effects of exercise, human trials do not. Evidence from non-human studies suggest that exercise might increase the levels of brain-derived neurotrophic factor, enhance cognitive appraisal, and improve perceived exertion. Overall, the paucity of data on the effectiveness of exercise in PTSD and mechanisms of action underscore the need for rigorous trials. Registration The protocol was registered with PROSPERO (ID:453615; 22.08.2023).
The value of mental science: we publish what matters.
Recent changes to US research funding are having far-reaching consequences that imperil the integrity of science and the provision of care to vulnerable populations. Resisting these changes, the BJPsych Portfolio reaffirms its commitment to publishing mental science and advancing psychiatric knowledge that improves the mental health of one and all.
The electroencephalography protocol for the Accelerating Medicines Partnership® Schizophrenia Program: Reliability and stability of measures.
Individuals at clinical high risk for psychosis (CHR) have variable clinical outcomes and low conversion rates, limiting development of novel and personalized treatments. Moreover, given risks of antipsychotic drugs, safer effective medications for CHR individuals are needed. The Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ) Program was launched to address this need. Based on past CHR and schizophrenia studies, AMP SCZ assessed electroencephalography (EEG)-based event-related potential (ERP), event-related oscillation (ERO), and resting EEG power spectral density (PSD) measures, including mismatch negativity (MMN), auditory and visual P300 to target (P3b) and novel (P3a) stimuli, 40-Hz auditory steady state response, and resting EEG PSD for traditional frequency bands (eyes open/closed). Here, in an interim analysis of AMP SCZ EEG measures, we assess test-retest reliability and stability over sessions (baseline, month-2 follow-up) in CHR (n = 654) and community control (CON; n = 87) participants. Reliability was calculated as Generalizability (G)-coefficients, and changes over session were assessed with paired t-tests. G-coefficients were generally good to excellent in both groups (CHR: mean = 0.72, range = 0.49-0.85; CON: mean = 0.71, range = 0.44-0.89). Measure magnitudes significantly (p
Mechanisms through which exercise reduces symptom severity and/or functional impairment in posttraumatic stress disorder (PTSD): Protocol for a living systematic review of human and non-human studies.
BACKGROUND: Exercise can play an important role in reducing symptom severity and improving functional impairment in patients with posttraumatic stress disorder (PTSD). However, the precise mechanisms underpinning the effect of exercise in PTSD management are not fully understood. This living systematic review aims to synthesize and triangulate the evidence from non-human and human studies to gain insight into the biopsychosocial mechanisms through which exercise reduces symptom severity and functional impairment. METHODS: Independent searches will be conducted in electronic databases to identify eligible studies. Two reviewers will independently conduct the study selection, data extraction, and risk of bias assessment. We will extract outcome data and variables that can act as effect modifiers or as mediators of the effect of exercise. For the non-human studies, outcome data will include the non-human equivalents of PTSD symptom clusters. For human studies, the primary outcome will be PTSD symptom severity. The secondary outcomes will be avoidance symptom severity, reexperiencing symptom severity, hyperarousal symptom severity, negative cognitions and mood severity, functional impairment, loss of PTSD diagnosis, and dropout rates.To explain the biopsychosocial mechanisms through which exercise affects the outcome of interest, we will extract effects that relate to the impact of exercise on potential mediating variables and the effect of the later outcomes. Comparison of within-study direct and indirect effects obtained from mediation analysis, when reported, will provide insight into the importance of the examined mediator.If appropriate, we will synthesize study results using meta-analyses. We will examine potential effect modifiers of the total exercise effect to understand better the impact of exercise on PTSD symptoms and function impairment (when possible). The evidence about the potential mediators of the association between exercise and PTSD-related outcomes will be considered in a consensus meeting when sufficient evidence is available. PROTOCOL REGISTRATION: PROSPERO-ID: 453615.