Evaluation of the efficacy of pimavanserin in the treatment of agitation and aggression in patients with Alzheimer's disease psychosis: a post hoc analysis

This is the final version. Available on open access from Wiley via the DOI in this recordObjectives Patients with Alzheimer's disease psychosis (ADP) commonly experience concomitant agitation and aggression. We investigated whether a reduction in ADP following pimavanserin treatment conferred a reduction in associated agitation and aggression. Methods ACP‐103‐019 was a 12‐week, randomized, double‐blind, placebo‐controlled study that evaluated the efficacy of pimavanserin (34 mg) in reducing psychotic symptoms in patients with ADP. The primary endpoint was change from baseline in Neuropsychiatric Inventory‐Nursing Home Version‐Psychosis Score (NPI‐NH‐PS) at week six. A post hoc analysis examined whether there was a greater reduction in agitation and aggression (NPI‐NH domain C [agitation/aggression] and Cohen‐Mansfield Agitation Inventory‐Short Form [CMAI‐SF]) in pimavanserin‐treated patients who experienced a reduction of hallucinations and delusions (psychosis responders defined as ≥50% reduction from baseline in NPI‐NH‐PS, week six) when compared with those who did not (nonresponders). Results Pimavanserin‐treated patients with ≥50% response in psychotic symptoms (n = 44) showed a greater improvement in agitation and aggression symptoms on the NPI‐NH domain C (week six, least squares mean [LSM] difference = −3.64, t = −4.69, P < .0001) and the CMAI‐SF (week six, LSM difference = −3.71, t = −2.01, P = .0483) than nonresponders (n = 32). Differences between psychosis responders and nonresponders were also observed in patients with more severe agitation and aggression at baseline on the NPI‐NH domain C (responders, n = 26; nonresponders, n = 13; week six, LSM difference = −3.03, t = −2.44, P = .019). Conclusions Patients with ADP, who show improvement in psychotic symptoms after pimavanserin treatment, also experience an improvement in concomitant agitation and aggression.ACADIA Pharmaceuticals Inc. (San Diego, CA

Cognitive decline in dementia with Lewy bodies: a 5-year prospective cohort study

OBJECTIVES: We report the cognitive decline in persons diagnosed with mild dementia with Lewy bodies (DLB) and mild Alzheimer's disease (AD) during 5 years of annual follow-ups. METHODS: Patients were recruited into the study from geriatric, psychiatric and neurology clinics in Western Norway during 2005–2013. They were diagnosed according to clinical consensus criteria, based on standardised clinical rating scales. Autopsy-based diagnoses were available for 20 cases. Cognitive decline for up to 5 years was assessed using the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Examination (MMSE). Survival analysis including Cox regression (time to reach severe dementia) and linear mixed-effects (lme) modelling were used to model the decline on MMSE. RESULTS: At least one follow-up assessment was available for 67 patients with DLB and 107 patients with AD, with a median follow-up time of 4.3 years. The time to reach severe dementia was significantly shorter in DLB (median 1793 days) compared with AD (1947 days; p=0.033), and the difference remained significant in the multiple Cox regression analysis (HR=2.0, p<0.02). In the adjusted lme model, MMSE decline was faster in DLB (annual decline 4.4 points) compared with AD (3.2 points; p<0.008). CONCLUSIONS: Our findings show that from the mild dementia stage, patients with DLB have a more rapid cognitive decline than in AD. Such prognostic information is vital for patients and families and crucial for planning clinical trials and enabling health economic modelling

An Intron 7 Polymorphism in APP Affects the Age of Onset of Dementia in Down Syndrome

People with Down syndrome (DS) develop Alzheimer's disease (AD) with an early age of onset. A tetranucleotide repeat, attt5−8, in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study. The authors examine the impact of this polymorphism in a larger cohort of individuals with DS. Adults with DS were genotyped for attt5−8 and APOE. The results were analysed with respect to the age of onset of dementia. The presence of three copies of the six-repeat allele resulted in onset of dementia seven years earlier than in the presence of other genotypes. Further study is essential to elucidate the mechanism by which this polymorphism functions, with an exciting opportunity to identify novel treatment targets relevant for people with DS and AD

Decadal Trends in Abundance, Size and Condition of Antarctic Toothfish in McMurdo Sound, Antarctica, 1972-2010

We report analyses of a dataset spanning 38 years of near-annual fishing for Antarctic toothfish Dissostichus mawsoni, using a vertical setline through the fast ice of McMurdo Sound, Antarctica, 1972-2010. This constitutes one of the longest biological time series in the Southern Ocean, and certainly the longest for any fish. Fish total length, condition and catch per unit effort (CPUE) were derived from the more than 5500 fish caught. Contrary to expectation, length-frequency was dominated by fish in the upper half of the industrial catch. The discrepancy may be due to biases in the sampling capabilities of vertical (this study) versus benthic (horizontal) fishing gear (industry long lines), related to the fact that only large Antarctic toothfish (more than 100 cm TL) are neutrally buoyant and occur in the water column. Fish length and condition increased from the early 1970s to the early 1990s and then decreased, related to sea ice cover, with lags of 8 months to 5 years, and may ultimately be related to the fishery (which targets large fish) and changes in the Southern Annular Mode through effects on toothfish main prey, Antarctic silverfish Pleuragramma antarcticum. CPUE was constant through 2001 and then decreased dramatically, likely related to the industrial fishery, which began in 1996 and which concentrates effort over the Ross Sea slope, where tagged McMurdo fish have been found. Due to limited prey choices and, therefore, close coupling among mesopredators of the Ross Sea, Antarctic toothfish included, the fishery may be altering the trophic structure of the Ross Sea

Unfolded protein response is activated in Lewy body dementias

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Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias

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Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients

© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.Introduction: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. Methods: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. Results: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.info:eu-repo/semantics/publishedVersio

Efficacy of Memantine for Agitation in Alzheimer’s Dementia: A Randomised Double-Blind Placebo Controlled Trial

Agitation in Alzheimer's disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD