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To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.
Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.
Community settings and care homes in 26 UK centers.
People with probable or possible Alzheimer’s disease and agitation.
Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.
One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.
On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.
Drug repositioning refers to the development of a drug for an indication other that in the marketing authorisation and drug repurposing is the use of known drugs for new indications. Both repositioning and repurposing are opportunities to complement traditional drug development and may shorten the time for a drug to reach the patient. This chapter provides a detailed overview of the pharmacological, preclinical, clinical and epidemiological evidence for four drugs or drug classes currently considered as the highest priority candidates for repurposing in Alzheimer’s disease: fasudil, phenserine, antiviral drugs and glucagon-like peptide 1 (GLP-1) analogs. In addition, key considerations on the future of repurposing are provided, including the role of transcriptional approaches and targeting risk genes and growth factors.
Mood disorders are characterised by pronounced symptom heterogeneity, which presents a substantial challenge both to clinical practice and research. Identification of subgroups of individuals with homogeneous symptom profiles that cut across current diagnostic categories could provide insights in to the transdiagnostic relevance of individual symptoms, which current categorical diagnostic systems cannot impart.
To identify groups of people with homogeneous clinical characteristics, using symptoms of manic and/or irritable mood, and explore differences between groups in diagnoses, functional outcomes and genetic liability.
We used latent class analysis on eight binary self-reported symptoms of manic and irritable mood in the UK Biobank and PROTECT studies, to investigate how individuals formed latent subgroups. We tested associations between the latent classes and diagnoses of psychiatric disorders, sociodemographic characteristics and polygenic risk scores.
Five latent classes were derived in UK Biobank (N = 42 183) and were replicated in the independent PROTECT cohort (N = 4445), including ‘minimally affected’, ‘inactive restless’, active restless’, ‘focused creative’ and ‘extensively affected’ individuals. These classes differed in disorder risk, polygenic risk score and functional outcomes. One class that experienced disruptive episodes of mostly irritable mood largely comprised cases of depression/anxiety, and a class of individuals with increased confidence/creativity reported comparatively lower disruptiveness and functional impairment.
Findings suggest that data-driven investigations of psychopathological symptoms that include sub-diagnostic threshold conditions can complement research of clinical diagnoses. Improved classification systems of psychopathology could investigate a weighted approach to symptoms, toward a more dimensional classification of mood disorders.
Older people describe positive and negative age-related changes, but we do not know much about what contributes to make them aware of these changes. We used content analysis to categorize participants’ written comments and explored the extent to which the identified categories mapped onto theoretical conceptualizations of influences on awareness of age-related change (AARC).
Cross-sectional observational study.
The study sample comprised 609 UK individuals aged 50 years or over (mean (SD) age = 67.9 (7.6) years), enrolled in the PROTECT study.
Between January and March 2019, participants provided demographic information, completed a questionnaire assessing awareness of age-related change (AARC-10 SF), and responded to an open-ended question asking them to comment on their responses.
While some of the emerging categories were in line with the existing conceptual framework of AARC (e.g. experiencing negative changes and attitudes toward aging), others were novel (e.g. engagement in purposeful activities or in activities that distract from age-related thoughts). Analysis revealed some of the thought processes involved in selecting responses to the questionnaire items, demonstrating different ways in which people make sense of specific items.
Results support the ability of the AARC questionnaire to capture perceived age-related changes in cognitive functioning, physical and mental health, and engagement in social activities and in healthy and adaptive behaviors. However, findings also suggest ways of enriching the theoretical conceptualization of how AARC develops and offer insights into interpretation of responses to measures of AARC.
Evidence linking subjective concerns about cognition with poorer objective cognitive performance is limited by reliance on unidimensional measures of self-perceptions of aging (SPA). We used the awareness of age-related change (AARC) construct to assess self-perception of both positive and negative age-related changes (AARC gains and losses). We tested whether AARC has greater utility in linking self-perceptions to objective cognition compared to well-established measures of self-perceptions of cognition and aging. We examined the associations of AARC with objective cognition, several psychological variables, and engagement in cognitive training.
Cross-sectional observational study.
The sample comprised 6056 cognitively healthy participants (mean [SD] age = 66.0 [7.0] years); divided into subgroups representing middle, early old, and advanced old age.
We used an online cognitive battery and measures of global AARC, AARC specific to the cognitive domain, subjective cognitive change, attitudes toward own aging (ATOA), subjective age (SA), depression, anxiety, self-rated health (SRH).
Scores on the AARC measures showed stronger associations with objective cognition compared to other measures of self-perceptions of cognition and aging. Higher AARC gains were associated with poorer cognition in middle and early old age. Higher AARC losses and poorer cognition were associated across all subgroups. Higher AARC losses were associated with greater depression and anxiety, more negative SPA, poorer SRH, but not with engagement in cognitive training.
Assessing both positive and negative self-perceptions of cognition and aging is important when linking self-perceptions to cognitive functioning. Objective cognition is one of the many variables – alongside psychological variables – related to perceived cognitive losses.
Loneliness and physical activity are important targets for research into the impact of COVID-19 because they have established links with mental health, could be exacerbated by social distancing policies, and are potentially modifiable. In this study, we aimed to identify whether loneliness and physical activity were associated with worse mental health during a period of mandatory social distancing in the UK.
Population-based observational cohort study.
Mental health data collected online during COVID-19 from an existing sample of adults aged 50 and over taking part in a longitudinal study of aging. All had comparable annual data collected between 2015 and 2019.
Three-thousand two-hundred and eighty-one participants aged 50 and over.
Trajectories of depression (measured by PHQ-9) and anxiety (measured by GAD-7) between 2015 and 2020 were analyzed with respect to loneliness, physical activity levels, and a number of socioeconomic and demographic characteristics using zero-inflated negative binomial regression.
In 2020, PHQ-9 score for loneliness, adjusted for covariates, was 3.23 (95% CI: 3.01–3.44), an increase of around 1 point on all previous years in this group and 2 points higher than people not rated lonely, whose score did not change in 2020 (1.22, 95% CI: 1.12–1.32). PHQ-9 was 2.60 (95% CI: 2.43–2.78) in people with decreased physical activity, an increase of .5 on previous years. In contrast, PHQ-9 in 2020 for people whose physical activity had not decreased was 1.66, 95% CI: 1.56−1.75, similar to previous years. A similar relationship was observed for GAD-7 though the absolute burden of symptoms lower.
After accounting for pre-COVID-19 trends, we show that experiencing loneliness and decreased physical activity are risk factors for worsening mental health during the pandemic. Our findings highlight the need to examine policies which target these potentially modifiable risk factors.
In this large population study, we set out to examine the profile of mild behavioral impairment (MBI) by using the Mild Behavioral Impairment Checklist (MBI-C) and to explore its factor structure when employed as a self-reported and informant-rated tool.
A total of 5,742 participant-informant dyads participated in the study.
Both participants and informants completed the MBI-C. The factor structure of the MBI-C was evaluated by exploratory factor analysis.
The most common MBI-C items, as rated by self-reported and informants, related to affective dysregulation (mood/anxiety symptoms), being present in 34% and 38% of the sample, respectively. The least common items were those relating to abnormal thoughts and perception (psychotic symptoms) (present in 3% and 6% of the sample, respectively). Only weak correlations were observed between self-reported and informant-reported MBI-C responses. Exploratory factor analysis for both sets of respondent answers indicated that a five-factor solution for the MBI-C was appropriate, reflecting the hypothesized structure of the MBI-C.
This is the largest and most detailed report on the frequency of MBI symptoms in a nondementia sample. The full spectrum of MBI symptoms was present in our sample, whether rated by self-reported or informant report. However, we show that the MBI-C performs differently in self-reported versus informant-reported situations, which may have important implications for the use of the questionnaire in clinic and research.
Understanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals.
Primary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia).
We found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms.
We observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.
Behavioral and psychological symptoms of dementia (BPSD) are nearly universal in dementia, a condition occurring in more than 40 million people worldwide. BPSD present a considerable treatment challenge for prescribers and healthcare professionals. Our purpose was to prioritize existing and emerging treatments for BPSD in Alzheimer's disease (AD) overall, as well as specifically for agitation and psychosis.
International Delphi consensus process. Two rounds of feedback were conducted, followed by an in-person meeting to ratify the outcome of the electronic process.
2015 International Psychogeriatric Association meeting.
Expert panel comprised of 11 international members with clinical and research expertise in BPSD management.
Consensus outcomes showed a clear preference for an escalating approach to the management of BPSD in AD commencing with the identification of underlying causes. For BPSD overall and for agitation, caregiver training, environmental adaptations, person-centered care, and tailored activities were identified as first-line approaches prior to any pharmacologic approaches. If pharmacologic strategies were needed, citalopram and analgesia were prioritized ahead of antipsychotics. In contrast, for psychosis, pharmacologic options, and in particular, risperidone, were prioritized following the assessment of underlying causes. Two tailored non-drug approaches (DICE and music therapy) were agreed upon as the most promising non-pharmacologic treatment approaches for BPSD overall and agitation, with dextromethorphan/quinidine as a promising potential pharmacologic candidate for agitation. Regarding future treatments for psychosis, the greatest priority was placed on pimavanserin.
This international consensus panel provided clear suggestions for potential refinement of current treatment criteria and prioritization of emerging therapies.
A planned subgroup analysis of a phase 3 study was performed to evaluate the efficacy and safety of pimavanserin (PIM) in Parkinson’s disease psychosis (PDP) patients withglobal cognitive impairment.
PDP is frequent, distressing, a leading cause of institutionalization, complicates PD management and is linked to increased morbidity, incident dementia and mortality. PIM, a selective serotonin receptor (5-HT2A) inverse agonist/antagonist, is newly FDA-approved for the treatment of hallucinations and delusions associated with PDP.
In Study 020, a 6-week FDA registration study, 199 patients with baseline Mini-Mental State Examination (MMSE) score ≥21, moderate-severe psychosis, and on stable PD meds, were randomized to PIM (34 mg/day) or placebo (PBO) for 6 weeks. This subgroup analysis evaluates efficacy and safety between two groups: those with MMSE total score ≥21 but <25 (cognitively impaired; equivalent to Montreal Cognitive Assessment [MoCA] score 15-19) and those with score ≥25 (cognitively normal; equivalent to MoCA score 20-30). Safety assessments were performed on the full safety dataset (i.e., three 6-week placebo-controlled studies) including 614 subjects (PIM=382, PBO=231).
Overall, patients in the PIM group experienced a statistically significant improvement in SAPS-PD scores from baseline to Day 43 compared with PBO (-5.79 vs. -2.73; p=0.001). In the subgroup analysis stratifying by baseline MMSE score, the change from baseline to Day 43 compared with PBO in the cognitively-impaired group (N=50) was numerically larger (-7.11 vs. -0.47; p=0.002). In the full safety dataset examining cognitively impaired patients, there were no between-group (PIM vs. PBO) differences in any treatment-emergent adverse event (TEAE) (57.6% vs. 56.1%) or serious TEAE (6.8% vs. 5.3%). The most common TEAEs occurring at ≥5% in either group were fall (7.4% vs.10.5%), confusional state (6.5% vs.1.8%), and orthostatic hypotension (0.0% vs. 8.8%).
In this subgroup analysis of PDP patients, the treatment effect of PIM on SAPS-PD was larger in the cognitively-impaired group, with similar TEAE and serious TEAE rates. These results hold promise for cognitively-impaired patients that will be further elucidated in future studies.
Clinical study was funded by ACADIA Pharmaceuticals Inc.
We comment on the conjecture by Parker et al. (2016) that Antarctic
toothfish recently returned to McMurdo Sound, arguing that this species never
departed. Instead, as deduced from a 40-year fishing effort, toothfish water column
prevalence became markedly reduced where bottom depths are <500 m, with research
continuing to show their presence on the bottom or above the bottom where depths are
deeper. We also counter arguments that toothfish departed, and remained absent,
during and following a five-year presence of mega-icebergs residing near the opposite
coast of Ross Island, the icebergs inhibiting or fomenting conditions that
discouraged toothfish presence in the Sound. Available analyses reveal that toothfish
movement into the Sound was probably not significantly affected, and additionally
that neither changes in hydrography nor in primary productivity in the Sound would
have been sufficient to impact toothfish presence through food web alteration. We
hypothesize that the local effect of predation by seals and whales and the regional
effect of a fishery targeting the largest toothfish (those neutrally buoyant and thus
capable of occupying upper levels of the water column) has resulted in the remaining
toothfish now being found predominantly closer to the bottom at greater depths.
To produce a practice guideline that includes a set of detailed consensus principles regarding the prescription of antipsychotics (APs) amongst people with dementia living in care homes.
We used a modified Delphi consensus procedure with three rounds, where we actively specified and optimized statements throughout the process, utilizing input from four focus groups, carried out in UK, Norway, and the Netherlands. This was done to identify relevant themes and a set of statement that experts agreed upon using the Research and Development/University of California at Los Angeles (RAND/UCLA) methodology.
A total of 72 scientific and clinical experts and 14 consumer experts reached consensus upon 150 statements covering five themes: (1) General prescription stipulations, (2) assessments prior to prescription, (3) care and treatment plan, (4) discontinuation, and (5) long-term treatment.
In this practice guideline, novel information was provided about detailed indication and thresholds of symptoms, risk factors, circumstances at which APs should be stopped or tapered, specific criteria for justifying long-term treatment, involvement of the multidisciplinary team, and family caregiver in the process of prescription. The practice guideline is based on formal consensus of clinicians and consumer experts and provides clinicians relevant practical information that is lacking in current guidelines.
The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD.
We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013.
We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of “clinically significant A/A.” There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials.
This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.
Gerhard et al clarify our understanding of mortality associated with antipsychotic use in people with dementia, by demonstrating a clear dose relationship and highlighting key questions regarding the relative mortality risk of different atypical antipsychotics. The study also suggests that antipsychotics may confer risks of increased mortality in older people without dementia.
Several important systematic reviews and meta-analyses focusing on psychosocial interventions have been undertaken in the last decade. However, they have not focused specifically on the treatment of individual behavioral and psychological symptoms of dementia (BPSD) with personalized interventions. This updated systematic review will focus on studies reporting the effect of personalized psychosocial interventions on key BPSD in care homes.
Systematic review of the evidence for psychosocial interventions for BPSD, focusing on papers published between 2000 and 2012. All care home and nursing home studies including individual and cluster randomized controlled trials (RCTs) and pre-/post-test studies with control conditions were included.
641 studies were identified, of which 40 fulfilled inclusion and exclusion criteria. There was good evidence to support the value of personalized pleasant activities with and without social interaction for the treatment of agitation, and reminiscence therapy to improve mood. The evidence for other therapies was more limited.
There is a growing body of evidence indicating specific effects of different personalized psychosocial interventions on individual BPSD and mood outcomes.