Cooperative Study-Clinical Global Impression Research Articles

Wrist-worn sensor-based measurements for drug effect detection with small samples in people with Lewy Body Dementia

IntroductionFew late-stage clinical trials in Parkinson's disease (PD) have produced evidence on the clinical validity of sensor-based digital measurements of daily life activities to detect responses to treatment. The objective of this study was to assess whether digital measures from patients with mild-to-moderate Lewy Body Dementia demonstrate treatment effects during a randomized Phase 2 trial. MethodsSubstudy within a 12-week trial of mevidalen (placebo vs 10, 30, or 75 mg), where 70/344 patients (comparable to the overall population) wore a wrist-worn multi-sensor device. ResultsTreatment effects were statistically significant by conventional clinical assessments (Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] sum of Parts I-III and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change [ADCS-CGIC] scores) in the full study cohort at Week 12, but not in the substudy. However, digital measurements detected significant effects in the substudy cohort at week 6, persisting to week 12. ConclusionsDigital measurements detected treatment effects in a smaller cohort over a shorter period than conventional clinical assessments. Trial registrationclinicaltrials.gov, NCT03305809

Abstract 483: External Counterpulsation Therapy (Renew™ NCP-5) For The Treatment Of Mild Cognitive Impairment Due To Alzheimer’s Disease Or Mild Dementia Of The Alzheimer’s Type

Introduction: Research is elucidating vascular impairment in the pathophysiology of Alzheimer’s disease (AD) and as a treatment target. NCP-5 is external counterpulsation (ECP) therapy approved for treating unstable angina and granted FDA Breakthrough Status for mild cognitive impairment (MCI) and AD. It increases cardiac output and improves endothelial function. A study was done to assess NCP-5 on cognitive function. Methods: Randomized, single-blind, sham-controlled; 10 US sites. Subjects 55-85 years (Montreal Cognitive Assessment score ≥11) were given NCP-5 (n=95) or active sham (n=95). Primary endpoint: mean change from baseline in Vascular Dementia Assessment Scale-cognitive subscale (VADAS-Cog) at 12, 18, and 24 weeks, powered for a 2-point change. Results: Primary endpoint met (change, -4.45 points); NCP-5 showed statistically significantly greater improvement from baseline vs active sham on VADAS-Cog. In subjects with type 2 diabetes (T2D; n=36), NCP-5 improved cognition from baseline (change, -17.01 points; p <0.005). NCP-5 was statistically significantly superior to active sham on Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change at weeks 12 (odds ratio [OR], 2.13; p =0.013) and 24 (OR, 2.56; p =0.002). NCP-5 had a statistically significant decrease on Neuropsychiatric Inventory Aggression Index vs active sham at week 24 ( p =0.041). Neuroimaging showed a decline in right hippocampal volume (HV) that was statistically significantly greater with NCP-5 at week 24 ( p =0.012) and at longitudinal assessment to 12 months ( p =0.008), possibly related to smaller HV seen at baseline with NCP-5. However, the decline in regional cerebral blood flow (rCBF) in the left hippocampus from baseline to month 12 and for the longitudinal assessment was statistically significantly less with NCP-5 than with active sham ( p =0.010 and 0.019, respectively). NCP-5 had a low-risk safety profile (10,644 exposures), and the most common AE was mild skin irritation/injury. Conclusions: Renew NCP-5 improved cognitive performance and global function, particularly in those with T2D. Findings support the role of targeting vascular dysfunction, specifically with NCP-5, for the treatment of MCI and mild dementia of the Alzheimer’s type.

Apathy in Dementia Methylphenidate Trial 2 (ADMET2): Results of a phase III, placebo‐controlled, double‐blind, 6‐month, multi‐center, randomized clinical trial

AbstractBackgroundApathy is one of the most common and debilitating neuropsychiatric symptoms of Alzheimer’s Disease (AD). Two previous trials that suggested methylphenidate was safe and efficacious involved only 60 participants each, followed for 6 weeks. A larger, longer‐lasting trial was required to confirm those promising findings.MethodsADMET 2 was a phase III, placebo‐controlled, 6‐month, multi‐center, randomized (1:1, 20 mg methylphenidate per day or placebo) clinical trial that randomized 200 participants with AD and apathy. Primary outcomes included: (1) the mean difference on the Neuropsychiatric Inventory Apathy (NPI‐A) subscale scores measured as change from baseline to 6 months, and/or (2) the odds of a rating of improvement on the modified AD Cooperative Study Clinical Global Impression of Change (ADCS‐CGIC) at month 6 compared with baseline. Secondary outcomes included change in cognition, safety, and cost‐effectiveness measured monthly for up to 6 months.Results200 individuals were randomized (65.8% were males; 34.2% were females; avg age=76 years; 75.3% had some college education or greater; mean Mini‐Mental State Examination score at baseline was 18.9). There was a larger difference in the methylphenidate group compared with the placebo group in NPI‐A score from baseline to 6 months using a mixed model (Mean difference = ‐1.25; 95% CI: ‐2.03, ‐0.47, p = 0.002) with the largest change observed during the first two months. At 6 months, the ADCS‐CGIC showed that 43.8% (39/89) of participants in the methylphenidate group improved compared with 35.2% (32/91) of study participants in the placebo group (odds ratio 1.90 (95% CI: 0.95, 3.84), favoring methylphenidate, but not reaching statistical significance (p = 0.071)). There were no significant differences in other assessments. The safety profile was similar between the two groups.ConclusionADMET 2 showed a small to medium benefit for methylphenidate in the treatment of apathy in AD. The effect was observed at 2 months and was sustained throughout the 6 months of the study. Adverse events were mild. These results support previous observations in smaller studies. Methylphenidate offers a viable treatment for patients suffering from apathy in AD.

Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease

Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality. To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease. This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included. Ten milligrams of methylphenidate, twice daily, vs matching placebo. The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life. Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups. This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease. ClinicalTrials.gov Identifier: NCT02346201.

TREATMENT PARAMETERS AND RATIONALE FOR THE USE OF ELECTROCONVULSIVE THERAPY FOR THE MANAGEMENT OF TREATMENT-REFRACTORY AGITATION IN ALZHEIMER'S DISEASE

TREATMENT PARAMETERS AND RATIONALE FOR THE USE OF ELECTROCONVULSIVE THERAPY FOR THE MANAGEMENT OF TREATMENT-REFRACTORY AGITATION IN ALZHEIMER'S DISEASE

Safety and tolerability of GRF6019 in mild-to-moderate Alzheimer's disease dementia.

IntroductionThis phase 2 trial evaluated the safety, tolerability, and feasibility of repeated infusions of the plasma fraction GRF6019 in mild‐to‐moderate Alzheimer's disease.MethodsIn this randomized, double‐blind, dose‐comparison trial, 47 patients were randomized 1:1 to receive daily infusions of 100 mL (n = 24) or 250 mL (n = 23) of GRF6019 for 5 consecutive days over two dosing periods separated by a treatment‐free interval of 3 months.ResultsThe mean (standard deviation [SD]) age of the enrolled patients was 74.3 (6.9), and 62% were women. Most adverse events (55%) were mild, with no clinically significant differences in safety or tolerability between the two dose levels. The mean (SD) baseline Mini‐Mental State Examination score was 20.6 (3.7) in the 100 mL group and 19.6 (3.7) in the 250 mL group; at 24 weeks, the within‐patient mean change from baseline was –1.0 points (95% confidence interval [CI], –3.1 to 1.1) in the 100 mL group and +1.5 points (95% CI, –0.4 to 3.3) in the 250 mL group. The within‐patient mean change from baseline on the Alzheimer's Disease Assessment Scale‐Cognitive subscale was –0.4 points (95% CI, –2.9 to 2.2) in the 100 mL group, while in the 250 mL group it was –0.9 points (95% CI, –3.0 to 1.2). The within‐patient mean change from baseline on the Alzheimer's Disease Cooperative Study‐Activities of Daily Living was –0.7 points in the 100 mL group (95% CI, –4.3 to 3.0) and –1.3 points (95% CI, –3.4 to 0.7) in the 250 mL group. The mean change from baseline on the Category Fluency Test, Clinical Dementia Rating Scale–Sum of Boxes, Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change, and Neuropsychiatric Inventory Questionnaire was similar for both treatment groups and did not show any worsening.DiscussionGRF6019 was safe and well tolerated, and patients experienced no cognitive decline and minimal functional decline. These results support further development of GRF6019.

Longitudinal Course of Agitation and Aggression in Patients with Alzheimer\u2019s Disease in a Cohort study: Methods, Baseline and Longitudinal Results of the A3C Study

BackgroundTo present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer’s Disease Cohort (A3C) study.ObjectivesThe central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings.DesignA3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities.SettingClinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design.ParticipantsAlzheimer’s Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities.MeasurementsClinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association “Provisional Diagnostic Criteria for Agitation”, socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed.ResultsA3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively −11.36 (Standard Error (SE)=1.32; p<0.001) and −6.72 (SE=0.77; p<0.001).ConclusionLittle is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer’s Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer’s Disease.

ELECTROCONVULSIVE THERAPY FOR THE TREATMENT OF ACUTE AGITATION AND AGGRESSION IN ALZHEIMER'S DEMENTIA (ECT-AD)

Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging, affecting approximately 5.4 million individuals in the US, and predicted to increase to 13.8 million by 2050. Occurring in over 90% of AD patients, neuropsychiatric symptoms such as agitation, depression and apathy, contribute to caregiver burden and increase patient morbidity and mortality. With no FDA-approved options available, treatments for severe agitation in people with advanced dementia are limited, with modest evidence for efficacy and substantial safety concerns. Behavioral therapies are recommended as first-line treatments for agitation in AD; however, they require substantial time to take effect and may be less efficacious for the most severely agitated patients. Psychotropic medications, especially antipsychotics, are widely used off-label to treat agitation in AD even with documented limitations in efficacy and safety concerns. Therefore, new treatments for severe agitation in AD refractory to standard interventions are timely and warranted. Randomized controlled trials have demonstrated the safety and efficacy of electroconvulsive therapy (ECT) for the treatment of severe psychiatric disorders of late life, including depression, mania and psychosis. Recently, small open label studies suggest efficacy and safety of ECT for agitation in individuals with AD who are refractory to standard therapies. The present randomized controlled trial builds upon prior work and aims to determine the efficacy and safety of ECT for severe agitation in moderate to severe stage AD, while also examining the durability of the acute treatment effect in an exploratory maintenance naturalistic design. Methods We describe an NIA-funded multi-site, single blind, randomized trial of ECT plus usual care (UC) versus Simulated-ECT (S-ECT) plus UC. We will enroll 200 inpatients with severe agitation and moderate to severe dementia, who have not responded well to prior trials of psychotropic medications. Our primary efficacy outcome measure is the Cohen Mansfield Agitation Inventory (CMAI), and the Neuropsychiatric Inventory – Clinician Version (NPI-C), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC), and Pittsburgh Agitation Scale (PAS) will be secondary measures. Safety and tolerability will be assessed with the Severe Impairment Battery – 8 item (SIB-8), the Confusion Assessment Method (CAM), and adverse event monitoring. Results Preliminary open-label data from our team suggests acute ECT treatment is safe and effective in reducing agitation in this population as measured by the CMAI, PAS, CGI, and adverse event monitoring. A multi-site, prospective case series investigated ECT treatment in 23 consecutive inpatients with dementia and severe agitation who did not benefit from standard behavioral interventions and pharmacotherapy. Eighteen of the 23 subjects experienced a significant reduction in agitation from baseline to discharge on the CMAI. In a retrospective chart review study of 16 patients undergoing ECT for agitation related to AD, only two experienced more than transient confusion post-ECT that required treatment, and no other clinically significant adverse events were noted in this group. We hypothesize ECT+UC will be more efficacious in reducing severe agitation in AD subjects than S-ECT+UC, as measured by our primary and secondary efficacy measures, and that there will be no difference in tolerability/safety outcomes for ECT+UC and S-ECT+UC as measured by cognitive decline (SIB-8), development of delirium (CAM), and serious adverse event monitoring. Conclusions This innovative study will fill a gap in the current clinical practice of treating severe agitation in AD using a rigorous methodological approach thus providing evidence for a new therapeutic application (severe agitation in AD) of a well-studied, established, and safe treatment (ECT). Study findings may demonstrate support for a new therapeutic use of ECT for severe agitation in AD. Successful management of neuropsychiatric symptoms reduces long-term care placement, decreases the risk of mortality, and enhances patient and caregiver quality-of-life. Such an approach has the potential to offer enormous relief to the substantial socioeconomic burden of AD-related behavioral disturbances. This research was funded by National Institute of Aging R01 AG061100-01

The Alzheimer's disease THErapy with NEuroaid (ATHENE) study protocol: Assessing the safety and efficacy of Neuroaid II (MLC901) in patients with mild-to-moderate Alzheimer's disease stable on cholinesterase inhibitors or memantine—A randomized, double-blind, placebo-controlled trial

BackgroundDementia is a large and growing health care burden globally, and its major cause is Alzheimer's disease (AD). MLC901 (Neuroaid II) is a simplified form of MLC601 (Neuroaid), a Traditional Chinese Medicine with neuroprotective and neuroproliferative properties in cellular and animal models of brain injury. MLC601 has been shown to modulate amyloid precursor protein (APP) processing in human neuroblastoma cell cultures and increase the levels of soluble APPα. In addition, MLC901 has been shown to reduce tau phosphorylation in vitro. Hence, MLC901 may have possible multimodal actions and a disease-modifying effect in AD. In previous clinical studies, MLC601 has shown promising effects in AD. ObjectiveTo investigate the safety and efficacy of MLC901 add-on therapy to standard treatment in mild-to-moderate probable AD patients stable on standard treatment and to evaluate if MLC901 has a disease-modifying effect in AD. MethodsThis is a 6-month randomized, double-blind, placebo-controlled trial in mild-to-moderate probable AD where MLC901 will be given as an add-on therapy to standard AD treatment, followed by an extension study for another 6 months, where all subjects will be treated with open-label MLC901 in addition to standard treatment. The primary outcome is safety as measured by adverse events, vital signs, electrocardiogram, laboratory tests, and physical and neurological examinations. Secondary outcomes evaluating cognition, behavior, and activities of daily living at various time points include the Alzheimer's Disease Assessment Scale–cognitive subscale, Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change, Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Mini–Mental State Examination. ConclusionMLC901 has the potential to improve cognition in AD patients. It may also have a role in delaying disease progression. This study will be the first to provide safety and efficacy data for MLC901 in mild-to-moderate probable AD patients already receiving standard therapy.

The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial

BackgroundAlzheimer’s disease (AD) is characterized not only by cognitive and functional decline, but also often by the presence of neuropsychiatric symptoms. Apathy, which can be defined as a lack of motivation, is one of the most prevalent neuropsychiatric symptoms in AD and typically leads to a worse quality of life and greater burden for caregivers. Treatment options for apathy in AD are limited, but studies have examined the use of the amphetamine, methylphenidate. The Apathy in Dementia Methylphenidate Trial (ADMET) found that treatment of apathy in AD with methylphenidate was associated with significant improvement in apathy in two of three outcome measures, some evidence of improvement in global cognition, and minimal adverse events. However, the trial only enrolled 60 participants who were followed for only 6 weeks. A larger, longer-lasting trial is required to confirm these promising findings.MethodsThe Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a phase III, placebo-controlled, masked, 6-month, multi-center, randomized clinical trial targeted to enroll 200 participants with AD and apathy. Participants are randomly assigned 1:1 to 20 mg methylphenidate per day prepared as four over-encapsulated tablets or to matching placebo. The primary outcomes include (1) the mean difference in the Neuropsychiatric Inventory Apathy subscale scores measured as change from baseline to 6 months, and (2) the odds of having a given rating or better on the modified AD Cooperative Study Clinical Global Impression of Change ratings at month 6 compared with the baseline rating. Other outcomes include change in cognition, safety, and cost-effectiveness measured at monthly follow-up visits up to 6 months.DiscussionGiven the prevalence of apathy in AD and its impact on both patients and caregivers, an intervention to alleviate apathy would be of great benefit to society. ADMET 2 follows on the promising results from the original ADMET to evaluate the efficacy of methylphenidate as a treatment for apathy in AD. With a larger sample size and longer follow up, ADMET 2 is poised to confirm or refute the original ADMET findings.Trial registrationClinicalTrials.gov, NCT02346201. Registered on 26 January 2015.

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease

New therapeutic approaches for Alzheimer disease (AD) are needed. To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

Structured physical exercise improves neuropsychiatric symptoms in acute dementia care: a hospital-based RCT

BackgroundThe primary objective of this trial is to investigate the effects of a short-term exercise program on neuropsychiatric signs and symptoms in acute hospital dementia care.MethodsWithin a hospital-based randomized controlled trial, the intervention group conducted a 2-week exercise program with four 20-min exercise sessions on 3 days per week. The control group conducted a social stimulation program. Effects on neuropsychiatric signs and symptoms were measured via the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change, the Neuropsychiatric Inventory, and the Cohen-Mansfield Agitation Inventory. The antipsychotic and sedative dosage was quantified by olanzapine and diazepam equivalents.ResultsEighty-five patients were randomized via minimization to an intervention group (IG) and a control group (CG). Seventy patients (82%) (mean age 80 years, 33 females, mean Mini Mental State Examination score 18.3 points) completed the trial. As compared to the CG (n = 35), the IG (n = 35) showed significantly reduced neuropsychiatric signs and symptoms. Especially, agitated behavior and lability improved. There were no between-group differences concerning antipsychotic and benzodiazepine medication.ConclusionsThis exercise program is easily applicable in hospital dementia care and significantly reduces neuropsychiatric signs and symptoms in patients suffering from predominantly moderate stages of dementia.Trial registrationGerman Clinical Trial Register DRKS00006740. Registered 28 October 2014.

Efficacy and Safety of Citalopram Compared to Atypical Antipsychotics on Agitation in Nursing Home Residents With Alzheimer Dementia

ObjectiveTo assess efficacy and safety of citalopram compared to quetiapine and olanzapine for the treatment of agitation in patients with Alzheimer disease (AD). DesignLongitudinal, 6-month study. SettingNursing home (NH). Participants75 NH residents with AD and agitation, randomized to citalopram (n = 25), quetiapine (n = 25), or olanzapine (n = 25). MeasurementsChanges in Neuropsychiatric Inventory (NPI) agitation subscale score and the modified Alzheimer Disease Cooperative Study–Clinical Global Impression of Change (mADCS-CGIC) were used to assess treatment efficacy. Participants were surveilled for adverse health outcomes. ResultsCitalopram treatment (30±5.8 mg/d) resulted in similar 6-month efficacy compared to both quetiapine (94.0±40.4 mg/d) and olanzapine (5.2±1.6 mg/d), lower occurrence of falls than olanzapine [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.68-0.97, P = .012], lower incidence of orthostatic hypotension than both quetiapine (OR = 0.80, 95% CI = 0.66-0.95, P = .032) and olanzapine (OR = 0.75, 95% CI = 0.69-0.91, P = .02), and less all-cause hospitalizations than both quetiapine (OR = 0.92, 95% CI = 0.88-0.95, P = .016) and olanzapine (OR = 0.78, 95% CI = 0.64-0.92, P = .004), after multiple adjustment for potentially confounding variables. No differences were observed for cognitive and functional decline, QTc prolongation, and infections. ConclusionsCitalopram resulted in similar efficacy and less adverse outcomes when compared to 2 atypical antipsychotics for treatment of agitation in NH residents with AD. Replication of these findings and assessment of long-term efficacy and safety of citalopram for treatment of neuropsychiatric symptoms in dementia are needed.

R- and S-citalopram concentrations have differential effects on neuropsychiatric scores in elders with dementia and agitation.

The aim was to determine the relationship between (R) and (S)-citalopram enantiomer exposure (AUC(0,24h)) and therapeutic response in agitated individuals greater than 60 years old with Alzheimer's dementia (AD). Citalopram enantiomer exposures (AUC(0,24h)) derived from an established population pharmacokinetic analysis were utilized to explore the relationship between (R)- and (S)-citalopram area under the curve (AUC(0,24)) and Mini-Mental State Examination (MMSE), Neurobehavioural Rating Scale-Agitation Subscale (NBRS-A), modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) and Neuropsychiatric Inventory Agitation subscale (NPIA) scores. Time dependent changes in these scores (disease progression) were accounted for prior to exploring the exposure effect relationship for each enantiomer. These relationships were evaluated using a non-linear-mixed effects modelling approach as implemented in nonmem v7.3. (S)-AUC(0,24h) and (R)-AUC(0,24h) each contributed to improvement in NBRS-A scores (k3(R) -0.502; k4(S) -0.712) as did time in treatment. However, increasing (R)-AUC(0,24h) decreased the probability of patient response (maximum Δ -0.182%/AUC(0,24h)) based on the CGIC while (S)-AUC(0,24h) improved the probability of response (maximum Δ 0.112%/AUC(0,24h)). (R)-AUC(0,24h) was also associated with worsening in MMSE scores (-0.5 points). Our results suggest that citalopram enantiomers contributed differentially to treatment outcomes. (R)-citalopram accounted for a greater proportion of the adverse consequences associated with racemic citalopram treatment in patients with AD including a decreased probability of treatment response as measured by the CGIC and a reduction in MMSE scores. The S-enantiomer was associated with increased probability of response based on the CGIC.

Rasagiline for mild cognitive impairment in Parkinson's disease: A placebo-controlled trial.

This study's aims were to determine the efficacy and tolerability of rasagiline, a selective monoamine oxidase inhibitor B, for PD patients with mild cognitive impairment. Patients on stable dopaminergic therapy were randomized to adjunct rasagiline 1 mg/day or placebo in this 24-week, double-blind, placebo-controlled, multisite study. The primary endpoint was mean change from baseline to week 24 on the Scales for Outcomes of Parkinson's Disease-Cognition total score. Key secondary measures included changes in cognition, activities of daily living, motor scores, and Clinical Global Impression of Change, as well as safety and tolerability measures. Of the 170 patients randomized, 151 (88.2%) completed the study. Change in Scales for Outcomes of Parkinson's Disease-Cognition scores were not significantly different in the rasagiline and placebo groups (adjusted mean: 1.6 [standard error {SE} = 0.5] vs. 0.8 [SE = 0.5] points; LS means difference = 0.8; 95% confidence interval: -0.48, 2.05; P = 0.22). There were no between-group differences in change in the MoCA (p=0.84) or Penn Daily Activities Questionnaire (P = 0.48) scores or in the distribution of Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change modified for mild cognitive impairment (P = 0.1). Changes in motor (UPDRS part III; P = 0.02) and activities of daily living (UPDRS part II; P < 0.001) scores favored rasagiline. Rasagiline was well tolerated; the most common adverse events in both groups were falls and dizziness. Rasagiline treatment in PD patients with mild cognitive impairment was not associated with cognitive improvement. Rasagiline did not worsen cognition, improved motor symptoms and activities of daily living, and was well tolerated in elderly cognitively impaired patients. © 2016 International Parkinson and Movement Disorder Society.

Rivastigmine Patch in Chinese Patients with Probable Alzheimer's disease: A 24-week, Randomized, Double-Blind Parallel-Group Study Comparing Rivastigmine Patch (9.5 mg/24 h) with Capsule (6 mg Twice Daily).

To compare the once-daily rivastigmine patch 9.5 mg/24 h (10 cm(2) ) versus twice-daily capsule (12 mg/day) in Chinese patients with probable Alzheimer's disease (AD) (mini-mental state examination [MMSE] scores of 10-20). The primary objective was to demonstrate the noninferiority of patch to capsule in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) change from baseline to 24 week. Secondary endpoints included cognition (MMSE), overall clinical response (Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change [ADCS-CGIC]), activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]), behavior (Neuropsychiatric Inventory [NPI-12]), and safety. Similar cognitive improvement was observed in both patch (n = 248) and capsule (n = 253) groups. Statistical noninferiority for ADAS-Cog was not established (least-square means difference, 0.1; 95% confidence interval, -1.2; 1.5). Considering all efficacy parameters into account, both treatments showed similar performance at Week 24. Treatment-related adverse events (AEs) were lower for patch (39.7%) compared with capsule (49.8%). Application site pruritus was reported in 10.9% of patients receiving patch; most cases were mild. Gastrointestinal AEs including nausea, vomiting, and diarrhea occurred less frequently in the patch group (15.8% vs. 28.7%). Rivastigmine patch 9.5 mg/24 h is effective and well tolerated in Chinese patients with probable AD.

Dextromethorphan Plus Quinidine Helps Quell Agitation

norepinephrine, and possibly other old with probable Alzheimer’s disease, group continued receiving the drug neurotransmitters. clinically significant agitation, and combination in stage 2, whereas the plaPublished in the Journal of the Mini-Mental State Examination score cebo group was stratified by response American Medical Association, the findof 8–28. Clinically significant agitation and re-randomized in a 1:1 ratio to ings are from a 10-week, 42-center was defined as poorly organized and dextromethorphan-quinidine (n = 59) double-blind, placebo-controlled study purposeless psychomotor activity and or placebo (n = 60). A Clinical Global led by Jeffrey L. Cummings, MD, ScD, aggressive verbal, aggressive physical, or Impressions-Severity (CGIS) agitation from the Cleveland Clinic Lou Ruvo nonaggressive physical behaviors. score up to 3 and a decrease of at least Center for Brain Health, Las Vegas In stage 1 of the trial, participants 25% in the Neuropsychiatric Inventory (JAMA 2015;314:1242–54.). Conducted were randomized in a 3:4 ratio to receive (NPI) Agitation/Aggression domain from August 2012 to August 2014, the dextromethorphan-quinidine (n = 93) or score constituted a response to treattrial enrolled 1,220 patients 50–90 years placebo (n = 127). The active treatment ment at the end of stage 1. Dextromethorphan Plus Quinidine Helps Quell Agitation

Change in agitation in Alzheimer's disease in the placebo arm of a nine-week controlled trial.

Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD). In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression. Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure. We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.

Citalopram for the Treatment of Agitation in Alzheimer Dementia: Genetic Influences.

To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory. We utilized data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures. Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks. Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation.

Evaluation of a hospital-based day-structuring exercise programme on exacerbated behavioural and psychological symptoms in dementia--the exercise carrousel: study protocol for a randomised controlled trial.

BackgroundConceptual reviews and observational studies describe a link between physical inactivity and behavioural disturbances in people with dementia. Consequently, treatment of these symptoms requires physical activation and pharmacological or physical immobilization should be avoided. The few trials that have been conducted in inpatient dementia care to investigate the effects of exercise on behavioural and psychological symptoms revealed inconsistent results. Due to a lack of evidence, there is a paucity of recommendations for physical activation in this stage of care. Therefore, this trial seeks to investigate the effects of a day-structuring exercise programme on behavioural and psychological symptoms as well as on circadian rhythms of patients with dementia, hospitalized because of their behavioural and psychological disturbances.Methods/DesignA single-centre randomised controlled trial will be conducted in three special dementia care units of an old age psychiatry hospital. Enrolled patients will receive either a 2-week exercise programme, or a 2-week social stimulation programme in addition to usual care. Due to the provision of four day-structuring exercise-sessions in the course of an intervention day, the exercise programme for the study group is called exercise-carrousel. Baseline and post-intervention assessment for the primary outcome variable - the overall effects on behavioural and psychological symptoms - will be measured by the Alzheimer's disease Cooperative Study-Clinical Global Impression of Change. The following objectives are set up as secondary outcomes: dimensions of the behavioural and psychological symptoms of dementia (BPSD) and caregiver burden, routine and on-demand psychotropic medication, patients’ motor behaviour, diurnal cortisol-levels from saliva probes and brain-derived neurotrophic factor-levels from blood serum.DiscussionIn order to be regarded as an important treatment option for behavioural and psychological symptoms, physical activation in inpatient hospital dementia care requires more evidence and appropriate recommendations. Respecting hospital routines and the intra-daily variability of the patients’ motivation and behavioural disturbances in the provision of exercise sessions could lead to higher exercise adherence and better effects on patients’ behavioural and psychological symptoms than former trials have presented. The concealment of allocation throughout the trial and the rating of individual exercise exertion present the key challenges and main limitations of this trial.Trial registrationDRKS00006740 (German Clinical Trial Register, date of registration: 28 October 2014).