Implementing a digital clinical decision support tool for side effects of antipsychotics: a focus group study

Background In medicine, algorithms can inform treatment decisions by combining the most up-to-date evidence about side effect profiles of medications, which are comparable in efficacy. Their use provides opportunities for improved shared clinician–patient decision-making when initiating therapy. We designed a decision support tool (DST) that incorporated the latest evidence regarding antipsychotic side effects. The tool allowed patients to select one side effect commonly associated with antipsychotics that they wished to avoid; the tool then provided a list of suggested medications and ones to avoid. Objective To explore qualitatively the acceptability and usefulness of the DST from the perspectives of patients and psychiatrists. Methods This qualitative study took place at a mental health and community hospital in Oxford, UK, in 2018. Four patients/carers and four psychiatrists were recruited to two focus groups to explore their perceptions of the tool. Data were thematically analysed. Findings Findings demonstrated a high degree of acceptability and potential usability of the DST for patients and psychiatrists. The main themes to emerge relating to the DST were ‘prescribing preferences and practices’, ‘consideration and awareness of side effects’, ‘app content, layout and accessibility’, ‘influence on clinical practice’ and ‘role in decision-making’. Conclusions A proof-of-concept clinical study will incorporate the recommendations produced from the findings into the tool’s design. Clinical implications Digital DSTs provide opportunities for the most up-to-date information on medication side effects to be used as the basis for shared clinician–patient decision-making. This tool has the potential to improve adherence to psychiatric medication, with benefits to clinical outcomes and healthcare resourcing

Cognitive and oculomotor performance in subjects with low and high schizotypy: implications for translational drug development studies

The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of \u27low schizotypes\u27 was significantly different from \u27high schizotypes\u27 with \u27average schizotypes\u27 having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes

Insulin resistance, age and depression’s impact on cognition in middle-aged adults from the PREVENT cohort

International audienceBackground Alzheimer’s disease (AD), type 2 diabetes mellitus (characterised by insulin resistance) and depression are significant challenges facing public health. Research has demonstrated common comorbidities among these three conditions, typically focusing on two of them at a time. Objective The goal of this study, however, was to assess the inter-relationships between the three conditions, focusing on mid-life (defined as age 40–59) risk before the emergence of dementia caused by AD. Methods In the current study, we used cross-sectional data from 665 participants from the cohort study, PREVENT. Findings Using structural equation modelling, we showed that (1) insulin resistance predicts executive dysfunction in older but not younger adults in mid-life, that (2) insulin resistance predicts self-reported depression in both older and younger middle-aged adults and that (3) depression predicts deficits in visuospatial memory in older but not younger adults in mid-life. Conclusions Together, we demonstrate the inter-relations between three common non-communicable diseases in middle-aged adults. Clinical implications We emphasise the need for combined interventions and the use of resources to help adults in mid-life to modify risk factors for cognitive impairment, such as depression and diabetes

An investigation into aripiprazole's partial D(2) agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers

Rationale: Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory. Objectives: We probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole’s prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole’s unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone. Method: A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning. Results: Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d’) and speeded reaction times. In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d’ and additionally had reduced errors of commission compared with placebo. Conclusion: Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade

PET tau and amyloid-β burden in mild Alzheimer's disease: divergent relationship with age, cognition and cerebrospinal fluid biomarkers

Background Combining PET amyloid-β and tau imaging may be critical for tracking disease progression in Alzheimer’s disease (AD). Objective We sought to characterize the relationship between amyloid-β and tau ligands as well as with other measures of pathology. Methods We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 years. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with amyloid-β ([18F]AV45) and tau ([18F]AV1451) ligands at baseline. Results 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical amyloid-β associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not amyloid-β. Conclusion The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker – the CSF total tau/Aβratio

Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives

There is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.We searched MEDLINE, Embase, PsycINFO and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.13 292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% (95% CI 35.2% to 51.3%), n=15 975, 63 studies), weakness (40.0% (95% CI 27.9% to 53.5%), n=221, 3 studies), fatigue (37.8% (95% CI 31.6% to 44.4%), n=21 101, 67 studies), dysgeusia (37.2% (95% CI 29.8% to 45.3%), n=13 686, 52 studies), myalgia (25.1% (95% CI 19.8% to 31.3%), n=66 268, 76 studies), depression (23.0% (95% CI 11.8% to 40.2%), n=43 128, 10 studies), headache (20.7% (95% CI 16.1% to 26.1%), n=64 613, 84 studies), anxiety (15.9% (5.6% to 37.7%), n=42 566, 9 studies) and altered mental status (8.2% (95% CI 4.4% to 14.8%), n=49 326, 19 studies). Heterogeneity for most clinical manifestations was high.Neurological and neuropsychiatric symptoms of COVID-19 in the pandemic's early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers

Investigating the brain’s neurochemical profile at midlife in relation to dementia risk factors

Changes in the brain’s physiology in Alzheimer’s disease are thought to occur early in the disease’s trajectory. In this study our aim was to investigate the brain’s neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40–59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia

Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer's disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-β burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-β in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer's disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual's in-life clinical vulnerability thus represent a tractable method of Alzheimer's disease modelling using clinical data in combination with cellular phenotypes

Persistent neuropsychiatric symptoms after COVID-19: a systematic review and meta-analysis.

The nature and extent of persistent neuropsychiatric symptoms after COVID-19 are not established. To help inform mental health service planning in the pandemic recovery phase, we systematically determined the prevalence of neuropsychiatric symptoms in survivors of COVID-19. For this pre-registered systematic review and meta-analysis (PROSPERO ID CRD42021239750), we searched MEDLINE, EMBASE, CINAHL and PsycINFO to 20 February 2021, plus our own curated database. We included peer-reviewed studies reporting neuropsychiatric symptoms at post-acute or later time-points after COVID-19 infection and in control groups where available. For each study, a minimum of two authors extracted summary data. For each symptom, we calculated a pooled prevalence using generalized linear mixed models. Heterogeneity was measured with I 2. Subgroup analyses were conducted for COVID-19 hospitalization, severity and duration of follow-up. From 2844 unique titles, we included 51 studies (n = 18 917 patients). The mean duration of follow-up after COVID-19 was 77 days (range 14-182 days). Study quality was most commonly moderate. The most prevalent neuropsychiatric symptom was sleep disturbance [pooled prevalence = 27.4% (95% confidence interval 21.4-34.4%)], followed by fatigue [24.4% (17.5-32.9%)], objective cognitive impairment [20.2% (10.3-35.7%)], anxiety [19.1% (13.3-26.8%)] and post-traumatic stress [15.7% (9.9-24.1%)]. Only two studies reported symptoms in control groups, both reporting higher frequencies in COVID-19 survivors versus controls. Between-study heterogeneity was high (I 2 = 79.6-98.6%). There was little or no evidence of differential symptom prevalence based on hospitalization status, severity or follow-up duration. Neuropsychiatric symptoms are common and persistent after recovery from COVID-19. The literature on longer-term consequences is still maturing but indicates a particularly high prevalence of insomnia, fatigue, cognitive impairment and anxiety disorders in the first 6 months after infection

Neuroimaging and Clinical Findings in Healthy Middle-Aged Adults With Mild Traumatic Brain Injury in the PREVENT Dementia Study

IMPORTANCE: Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI.OBJECTIVE: To assess whether TBI are associated with and interact with midlife changes in neuroimaging and clinical features in otherwise healthy individuals.DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis used baseline data from the PREVENT Dementia program collected across 5 sites in the UK and Ireland between 2014 and 2020. Eligible participants were cognitively healthy midlife adults aged between 40 and 59 years. Data were analyzed between January 2023 and April 2024.EXPOSURE: Lifetime TBI history was assessed using the Brain Injury Screening Questionnaire.MAIN OUTCOMES AND MEASURES: Cerebral microbleeds and other markers of cerebral small vessel disease (white matter hyperintensities [WMH], lacunes, perivascular spaces) were assessed on 3T magnetic resonance imaging. Clinical measures were cognition, sleep, depression, gait, and cardiovascular disease (CVD) risk, assessed using Computerized Assessment of Information Processing (COGNITO), Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, clinical interviews, and the Framingham Risk Score, respectively.RESULTS: Of 617 participants (median [IQR] age, 52 [47-56] years; 380 female [61.6%]), 223 (36.1%) had a history of TBI. TBI was associated with higher microbleed count (β = 0.10; 95% CI, 0.01-0.18; P = .03), with a dose-response association observed with increasing number of TBI events (β = 0.05; 95% CI, 0.01-0.09; P = .03). Conversely, TBI was not associated with other measures of small vessel disease, including WMH. Furthermore, TBI moderated microbleed associations with vascular risk factors and clinical outcomes, such that associations were present only in the absence of TBI. Importantly, observations held when analyses were restricted to individuals reporting only mild TBI.CONCLUSIONS AND RELEVANCE: In this cross-sectional study of healthy middle-aged adults, detectable changes in brain imaging and clinical features were associated with remote, even mild, TBI in the general population. The potential contribution of vascular injury to TBI-related neurodegeneration presents promising avenues to identify potential targets, with findings highlighting the need to reduce TBI through early intervention and prevention in both clinical care and policymaking.</p