A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status.

AIMS: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N-desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight. METHODS: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993-2017. RESULTS: There were 17 787 measurements from 5960 patients (4315 male) aged 18-86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h-1 between 20 and 80 years. Model-based dose predictions to attain a predose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in nonsmoking, White males weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females, and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between 20 and 80 years. CONCLUSION: The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain predose clozapine concentration of 0.35 mg L-1 . The analysis was, however, limited by the absence of data on clinical outcome and future studies are required to determine optimal predose concentrations specifically in those aged over 65 years.

Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.

Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.

Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer's disease.

Blood-brain barrier (BBB) dysfunction may be involved in the increased sensitivity of Alzheimer's disease (AD) patients to antipsychotics, including amisulpride. Studies indicate that antipsychotics interact with facilitated glucose transporters (GLUT), including GLUT1, and that GLUT1 BBB expression decreases in AD. We tested the hypotheses that amisulpride (charge: +1) interacts with GLUT1, and that BBB transport of amisulpride is compromised in AD. GLUT1 substrates, GLUT1 inhibitors and GLUT-interacting antipsychotics were identified by literature review and their physicochemical characteristics summarised. Interactions between amisulpride and GLUT1 were studied using in silico approaches and the human cerebral endothelial cell line, hCMEC/D3. Brain distribution of [3H]amisulpride was determined using in situ perfusion in wild type (WT) and 5xFamilial AD (5xFAD) mice. With transmission electron microscopy (TEM) we investigated brain capillary degeneration in WT mice, 5xFAD mice and human samples. Western blots determined BBB transporter expression in mouse and human. Literature review revealed that, although D-glucose has no charge, charged molecules can interact with GLUT1. GLUT1 substrates are smaller (184.95±6.45g/mol) than inhibitors (325.50±14.40g/mol) and GLUT-interacting antipsychotics (369.38±16.04). Molecular docking showed beta-D-glucose (free energy binding: -15.39kcal/mol) and amisulpride (-29.04kcal/mol) interact with GLUT1. Amisulpride did not affect [14C]D-glucose hCMEC/D3 accumulation. [3H]amisulpride uptake into the brain (except supernatant) of 5xFAD mice compared to WT remained unchanged. TEM revealed brain capillary degeneration in human AD. There was no difference in GLUT1 or P-glycoprotein BBB expression between WT and 5xFAD mice. In contrast, caudate P-glycoprotein, but not GLUT1, expression was decreased in human AD capillaries versus controls. This study provides new details about the BBB transport of amisulpride, evidence that amisulpride interacts with GLUT1 and that BBB transporter expression is altered in AD. This suggests that antipsychotics could potentially exacerbate the cerebral hypometabolism in AD. Further research into the mechanism of amisulpride transport by GLUT1 is important for improving antipsychotics safety.

Longitudinal decline in striatal dopamine transporter binding in Parkinson's disease: associations with apathy and anhedonia.

BACKGROUND: Motivational symptoms such as apathy and anhedonia are common in Parkinson's disease (PD), respond poorly to treatment, and are hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in PD but the association has never been examined longitudinally. We investigated whether progression of dopaminergic dysfunction was associated with emergent apathy and anhedonia symptoms in PD. METHODS: Longitudinal cohort study of 412 newly diagnosed patients with PD followed over 5 years as part of the Parkinson's Progression Markers Initiative cohort.Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item Geriatric Depression Scale (GDS-15) and part I of the MDS-Unified Parkinson's Disease Rating Scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging. RESULTS: Linear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio (SBR) and apathy/anhedonia symptoms, which emerged as PD progressed (interaction:ß=-0.09, 95% CI (-0.15 to -0.03), p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average 2 years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) (ß=-0.06, 95% CI (-0.13 to 0.01)) or motor symptoms (ß=0.20, 95% CI (-0.25 to 0.65)). CONCLUSIONS: Our findings support a central role for dopaminergic dysfunction in motivational symptoms in PD. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies.

Association Between False Memories and Delusions in Alzheimer Disease.

Importance: Understanding the mechanisms of delusion formation in Alzheimer disease (AD) could inform the development of therapeutic interventions. It has been suggested that delusions arise as a consequence of false memories. Objective: To investigate whether delusions in AD are associated with false recognition, and whether higher rates of false recognition and the presence of delusions are associated with lower regional brain volumes in the same brain regions. Design, Setting, and Participants: Since the Alzheimer's Disease Neuroimaging Initiative (ADNI) launched in 2004, it has amassed an archive of longitudinal behavioral and biomarker data. This cross-sectional study used data downloaded in 2020 from ADNI participants with an AD diagnosis at baseline or follow-up. Data analysis was performed between June 24, 2020, and September 21, 2021. Exposure: Enrollment in the ADNI. Main Outcomes and Measures: The main outcomes included false recognition, measured with the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and the Rey Auditory Verbal Learning Test (RAVLT) and volume of brain regions corrected for total intracranial volume. Behavioral data were compared for individuals with delusions in AD and those without using independent-samples t tests or Mann-Whitney nonparametric tests. Significant findings were further explored using binary logistic regression modeling. For neuroimaging data region of interest analyses using t tests, Poisson regression modeling or binary logistic regression modeling and further exploratory, whole-brain voxel-based morphometry analyses were carried out to explore the association between regional brain volume and false recognition or presence of delusions. Results: Of the 2248 individuals in the ADNI database, 728 met the inclusion criteria and were included in this study. There were 317 (43.5%) women and 411 (56.5%) men. Their mean (SD) age was 74.8 (7.4) years. The 42 participants with delusions at baseline had higher rates of false recognition on the ADAS-Cog 13 (median score, 3; IQR, 1 to 6) compared with the 549 control participants (median score, 2; IQR, 0 to 4; U = 9398.5; P = .04). False recognition was not associated with the presence of delusions when confounding variables were included in binary logistic regression models. An ADAS-Cog 13 false recognition score was inversely associated with left hippocampal volume (odds ratio [OR], 0.91 [95% CI, 0.88-0.94], P < .001), right hippocampal volume (0.94 [0.92-0.97], P < .001), left entorhinal cortex volume (0.94 [0.91-0.97], P < .001), left parahippocampal gyrus volume (0.93 [0.91-0.96], P < .001), and left fusiform gyrus volume (0.97 [0.96-0.99], P < .001). There was no overlap between locations associated with false recognition and those associated with delusions. Conclusions and Relevance: In this cross-sectional study, false memories were not associated with the presence of delusions after accounting for confounding variables, and no indication for overlap of neural networks for false memories and delusions was observed on volumetric neuroimaging. These findings suggest that delusions in AD do not arise as a direct consequence of misremembering, lending weight to ongoing attempts to delineate specific therapeutic targets for treatment of psychosis.

Neuropsychiatric features of Parkinson's disease in the era prior to the use of dopaminergic therapies.

BACKGROUND: Psychosis in Parkinson's disease includes hallucinations and delusions. Other non-psychotic neuropsychiatric features include depression, anxiety and apathy. There is currently controversy over whether psychosis in Parkinson's is an intrinsic part of the disorder or the result of dopaminergic medications. This study aimed to examine a historical cohort of individuals with Parkinson's prior to the use of dopaminergic therapy to assess the prevalence of psychotic and other neuropsychiatric features. METHODS: The case notes of patients with Parkinson's disease admitted to the National Hospital for Neurology and Neurosurgery, London between 1924 and 1946 were examined. Demographic and clinical variables were extracted along with any neuropsychiatric features. Cases meeting criteria for encephalitis lethargica were excluded. RESULTS: 115 cases of individuals with Parkinson's disease were identified. 58 (41.7%) were female. Mean age was 54.0 (SD 9.6) years and mean time since Parkinson's diagnosis was 5.3 (SD 5.7) years. No individuals met criteria for encephalitis lethargica. No cases of hallucinations or delusions were reported. There was one case of an illusion in a patient who was using anticholinergic medication. Other neuropsychiatric features reported were sleep disorder (present in 10, 8.7%), depression (8, 7.0%), memory impairment (5, 4.3%), impulsivity (4, 3.5%), bradyphrenia (4, 3.5%), impaired attention (3, 2.6%), anxiety (1, 0.9%), fatigue (1, 0.9%) and apathy (1, 0.9%). CONCLUSIONS: Prior to the use of dopaminergic therapies, patients with Parkinson's disease admitted to hospital rarely, if ever, reported psychotic symptoms, although other neuropsychiatric symptoms were more prevalent. The main limitation is that a lack of systematic enquiry about psychotic symptoms may have resulted in underreporting.

Clozapine: Dose, Sex, Ethnicity, Smoking Habit, Age, Body Weight, and Plasma Clozapine and N -Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice.

BACKGROUND: Guidance on clozapine dosing in treatment refractory schizophrenia is based largely on data from young adult male White patients. AIM: This study aimed to audit the plasma clozapine and N -desmethylclozapine (norclozapine) concentrations attained in male and female patients of different ethnicity and smoking habit. METHOD: The effect of dose, sex, ethnicity, age, body weight, and smoking habit on plasma clozapine and norclozapine concentrations were studied using data from a therapeutic drug monitoring service, 1993 to 2017. RESULTS: There were 371,610 samples (48,098 patients, 32,855 male). Ethnicity was recorded for 763 Afro-Caribbean, 536 Asian, and 7940 White patients. Males were prescribed significantly higher median doses than females but attained significantly lower median plasma clozapine and norclozapine concentrations. Asian and Afro-Caribbean males were prescribed significantly lower and higher median doses, respectively, than White males but attained significantly higher and lower median plasma clozapine and norclozapine concentrations, respectively. Data from 78,431 samples (23,516 patients) were analyzed using a linear mixed model. The predicted dose to attain a predose plasma clozapine concentration of 0.35 mg/L in a nonsmoking White male aged 40 years, with weight of 70 kg, and plasma clozapine-norclozapine ratio of 1.32 was 344 mg/d (95% confidence interval, 227-526 mg/d). The predicted dose was 33% higher and 20% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. In all cases, the predicted dose was increased by 36% in smokers and decreased by 22% in females. CONCLUSIONS: Research is needed to further investigate the complex relationships between dose, sex, ethnicity, plasma clozapine and norclozapine concentrations, and clinical outcome such as weight gain.

Guiding safer risperidone prescribing in Alzheimer's disease with therapeutic drug monitoring.

Previous analysis of pharmacokinetic data on risperidone-treated patients with dementia predicted that 20% had concentration-to-dose (C/D) ratios of the active moiety (risperidone and 9-hydroxy(OH)-risperidone) above 14 ng/mL per mg/day, which were in turn associated with a greater risk of extrapyramidal side effects. This study aimed to further explore risperidone pharmacokinetics in a second dataset. Nonlinear mixed effects modelling, using a Bayesian approach, was applied to data from a randomized controlled trial of risperidone in people with dementia. Covariates included age and glomerular filtration rate (GFR). Age had a significant effect on risperidone clearance (ß = -1.5) and GFR on 9-OH-risperidone clearance (ß = 0.2). The model predicted that 26.2% (95% confidence interval 18.6-32.6%) had C/D ratios above 14 ng/mL per mg/day. These findings confirm the importance of age-related risperidone dose adjustments and argue strongly for therapeutic drug monitoring in the initial stages of treatment to identify those at greatest risk of toxicity.

Clinical utility of cerebrospinal fluid biomarkers in the evaluation of cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: The analytical and clinical validity of cerebrospinal (CSF) biomarkers has been extensively researched in dementia. Further work is needed to assess the ability of these biomarkers to improve diagnosis, management and health outcomes in the clinical setting OBJECTIVES: To assess the added value and clinical utility of CSF biomarkers in the diagnostic assessment of cognitively impaired patients under evaluation for Alzheimer's disease (AD). METHODS: Systematic literature searches of Medline, EMBASE, PsycINFO and Web of Science research databases were conducted on 17 December 2022. Data from relevant studies were extracted and independently screened for quality using a tool for bias. Clinical utility was measured by clinicians' changes in diagnosis, diagnostic confidence and patient management (when available), after their examination of patients' CSF biomarkers. Cost-effectiveness was assessed by consideration of additional cost per patient and quality-adjusted life years. RESULTS: Searches identified 17 studies comprising 2090 patient participants and 593 clinicians. The meta-analysis revealed that clinicians' use of CSF biomarkers resulted in a pooled percentage change in diagnosis of 25% (95% CI 14 to 37), an increase in diagnostic confidence of 14% (95% CI 9 to 18) and a pooled proportion of patients whose management changed of 31% (95% CI 12 to 50). CSF biomarkers were deemed cost-effective, particularly in memory services, where pre-test AD prevalence is higher compared with a primary care setting. CONCLUSIONS: CSF biomarkers can be a helpful additional diagnostic tool for clinicians assessing patients with cognitive impairment. In particular, CSF biomarkers consistently improved clinicians' confidence in diagnosing AD and influenced on diagnostic change and patient management. Further research is needed to study the clinical utility of blood-based biomarkers in the clinical setting.

Changes in dynamic transitions between integrated and segregated states underlie visual hallucinations in Parkinson's disease.

Hallucinations are a core feature of psychosis and common in Parkinson's. Their transient, unexpected nature suggests a change in dynamic brain states, but underlying causes are unknown. Here, we examine temporal dynamics and underlying structural connectivity in Parkinson's-hallucinations using a combination of functional and structural MRI, network control theory, neurotransmitter density and genetic analyses. We show that Parkinson's-hallucinators spent more time in a predominantly Segregated functional state with fewer between-state transitions. The transition from integrated-to-segregated state had lower energy cost in Parkinson's-hallucinators; and was therefore potentially preferable. The regional energy needed for this transition was correlated with regional neurotransmitter density and gene expression for serotoninergic, GABAergic, noradrenergic and cholinergic, but not dopaminergic, receptors. We show how the combination of neurochemistry and brain structure jointly shape functional brain dynamics leading to hallucinations and highlight potential therapeutic targets by linking these changes to neurotransmitter systems involved in early sensory and complex visual processing.

Plasma Clozapine and Norclozapine After Use of Either Crushed Tablets or Suspension Compared With Tablets.

BACKGROUND: With clozapine, either crushed tablets suspended in an aqueous medium or proprietary suspension is sometimes prescribed as an alternative to tablets, but bioequivalence data are scant. METHODS: We compared clozapine dose, and plasma clozapine and N -desmethylclozapine (norclozapine) concentrations after use of either tablets or crushed tablets/suspension in samples submitted for clozapine therapeutic drug monitoring, 1993 to 2017. RESULTS: There were 846 patients (1646 samples) given crushed tablets/suspension and 6065 patients (10,779 samples) given tablets. The median dose (mg d -1 ) was significantly higher in men (500 vs 450) and women (500 vs 400) given crushed tablets/suspension, but the median plasma clozapine and norclozapine concentrations (mg L -1 ) were significantly lower (men: 0.29 and 0.22 vs 0.39 and 0.28; women: 0.35 and 0.26 vs 0.50 and 0.32, respectively). A subgroup of 480 patients was prescribed either crushed tablets/suspension (1016 samples) or tablets (1259 samples) at different times. The median dose was again significantly higher in men (500 vs 500) and women (500 vs 450), but the median plasma clozapine and norclozapine concentrations were significantly lower (men: 0.29 and 0.22 vs 0.32 and 0.24; women: 0.30 and 0.24 vs 0.38 and 0.29, respectively). IMPLICATIONS: Poor adherence, sedimentation of suspension before use, and incomplete dosage are potential contributors to the lower median plasma clozapine and norclozapine concentrations observed after use of either crushed clozapine tablets or suspension as compared with tablets. Those administering crushed tablets/suspension should be aware of these factors.

Selective 5HT3 antagonists and sensory processing: a systematic review.

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson's disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

Paranoid and misidentification subtypes of psychosis in dementia.

This study aimed to review the neurobiological and neuropsychological correlates of paranoid (persecutory delusions) and misidentification (misidentification delusions and/or hallucinations) subtypes of psychosis in dementia, to establish if they represent distinct subphenotypes. Nine studies were eligible, all included patients with Alzheimer's disease. Greater global cognitive deficits and an accelerated global cognitive decline were observed in the misidentification subtype. Neuroimaging studies showed more marked volume loss in multiple regions in patients with the misidentification subtype, including those involved in object recognition and the processing of information on spatial and temporal context. A single study found greater impairment in visual sustained attention and object recognition in the misidentification subtype. The small number of studies and methodological heterogeneity limit interpretation of the findings. Nevertheless, these findings would tentatively suggest that there may be additional or accelerated pathological change in functional networks involved in visuoperceptual processing in the misidentification subtype. This should be further explored in prospective studies and the investigation extended to other forms of dementia, to gain a transdiagnostic perspective.

Disrupted reward processing in Parkinson's disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis.

BACKGROUND: Neuropsychiatric symptoms are common in Parkinson's disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICDs). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy. METHODS: The Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to 5 November 2020. Studies reporting reward processing task performance by patients with PD and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardised mean difference (SMD) scores and meta-analysed using a random effects model. RESULTS: We identified 55 studies containing 2578 participants (1638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: option valuation (n=12), reinforcement learning (n=37) and reward response vigour (n=6). Across all studies, patients with PD on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95% CI 0.14 to 0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95% CI 0.29 to 0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on option valuation (SMD=0.57, 95% CI 0.39 to 0.75) and reward response vigour (SMD=0.36, 95% CI 0.13 to 0.59) tasks. However, the opposite applied for reinforcement learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95% CI 0.25 to 0.65) but not off-medication (SMD=0.28, 95% CI -0.03 to 0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared tonon-ICD patients (SMD=-0.02, 95% CI -0.43 to 0.39). CONCLUSION: Reward processing disruption in PD differs according to subcomponent and dopamine medication state, and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes.

Pharmacological treatment trials of agitation in Alzheimer's disease: A systematic review of ClinicalTrials.gov registered trials.

INTRODUCTION: There is increasing emphasis on the importance of optimizing and standardizing clinical trials of agitation in Alzheimer's disease (AD), but the risks of bias arising from published trials and the number and design of unpublished studies are poorly understood. METHODS: Using the ClinicalTrials.gov database, we systematically reviewed all registered investigational clinical trials for agitation in AD to describe the landscape of agitation drug treatment trials and to assess their quality and generalizability. RESULTS: We included 52 clinical studies registered over the past 25 years. Within published randomized controlled trials (RCTs), there was a high rate of participant dropout, poor reporting of randomization procedures, and inconsistent definitions of the sample included for analysis. There was also evidence of publication and funder bias. DISCUSSION: We discuss factors that limit the internal and external validity of published RCTs and make additional recommendations for the conduct and reporting of future clinical trials of agitation in AD.

Towards safer risperidone prescribing in Alzheimer's disease.

BACKGROUND: In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to 'use the lowest possible dose' of antipsychotic drugs, but provide no information on optimal dosing. AIMS: This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548). METHOD: A statistical model, which described the concentration-time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and 'active moiety' (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS. RESULTS: The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann-Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance. CONCLUSIONS: Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.

Neuropsychiatric symptoms in limbic-predominant age-related TDP-43 encephalopathy and Alzheimer's disease.

There is clinical overlap between presentations of dementia due to limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease. It has been suggested that the combination of Alzheimer's disease neuropathological change (ADNC) and LATE neuropathological changes (LATE-NC) is associated with greater neuropsychiatric symptom burden, compared to either pathology alone. Longitudinal Neuropsychiatric Inventory and psychotropic medication prescription data from neuropathologically diagnosed pure ADNC (n = 78), pure LATE-NC (n = 14) and mixed ADNC/LATE-NC (n = 39) brain bank donors were analysed using analysis of variance and linear mixed effects regression models to examine the relationship between diagnostic group and neuropsychiatric symptom burden. Nearly all donors had dementia; three (two pure LATE-NC and one pure ADNC) donors had mild cognitive impairment and another two donors with LATE-NC did not have dementia. The mixed ADNC/LATE-NC group was older than the pure ADNC group, had a higher proportion of females compared to the pure ADNC and LATE-NC groups, and had more severe dementia versus the pure LATE-NC group. After adjustment for length of follow-up, cognitive and demographic factors, mixed ADNC/LATE-NC was associated with lower total Neuropsychiatric Inventory and agitation factor scores than pure ADNC, and lower frontal factor scores than pure LATE-NC. Our findings indicate that concomitant LATE pathology in Alzheimer's disease is not associated with greater neuropsychiatric symptom burden. Future longitudinal studies are needed to further investigate whether mixed ADNC/LATE-NC may be protective against agitation and frontal symptoms in dementia caused by Alzheimer's disease or LATE pathology.