Cohen-Mansfield Agitation Inventory Total Score Research Articles

Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's disease: a meta-analysis of randomized controlled trials.

Recent randomized controlled trials (RCTs) have shown a benefit of brexpiprazole in managing agitation in patients with Alzheimer's disease (AD). However, its efficacy and safety remain unclear. We systematically searched PubMed, Embase, and Cochrane Library for RCTs comparing brexpiprazole with placebo in patients with agitation and AD. Three studies comprising 1,048 patients were included. In patients with agitation and AD, brexpiprazole significantly improved the Cohen-Mansfield Agitation Inventory total score (CMAI) at any dose (MD -3.05; 95% CI -5.12, -0.98; p < 0.01; I2 = 19%) and at 2mg (MD -4.36; 95% CI -7.02, -1.70; p < 0.01; I2 = 0%) over 12weeks. Brexpiprazole at any dose and 2mg also showed benefit in the Clinical Global Impression - Severity of illness (CGI-S) score as related to agitation over 12weeks (MD -0.20; 95% CI -0.36, -0.05; p < 0.01; I2 = 35%). There is no significant difference between the groups in the incidence of at least one treatment-emergent adverse events (TEAEs; RR 1.14; 95% CI 0.95, 1.37; p = 0.16; I2 = 45%) and all-cause mortality (RR 1.99; 95% CI 0.37, 10.84; p = 0.42; I2 = 0%). Brexpiprazole at any dose significantly increased the Simpson-Angus Scale (SAS; MD 0.47; 95% CI 0.28, 0.66; p < 0.01). Our results suggest that brexpiprazole is more efficacious than placebo in the treatment of agitation in AD patients. Further studies are still necessary to confirm long-term effects of brexpiprazole.Prospero registry: CRD42023486694.

Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia

Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment. To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia. This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio. The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events. A total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo. In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population. ClinicalTrials.gov Identifier: NCT03548584.

Med Check: No Accelerated Pathway for Donanemab and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: No Accelerated Pathway for Donanemab and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:24 Feb 2023https://doi.org/10.1176/appi.pn.2023.03.3.2FDA Declines Accelerated Approval for DonanemabThe U.S. Food and Drug Administration (FDA) has declined to accept Eli Lilly’s Alzheimer’s biologic donanemab into the accelerated approval pathway, the company announced in January. Donanemab is a monoclonal antibody that targets beta amyloid buildup in the brain, which is thought to contribute to Alzheimer’s disease.In its complete response letter to the accelerated approval application, the FDA specifically requested that Eli Lilly provide data from at least 100 patients who received a minimum of 12 months of continued treatment on donanemab.The FDA had previously granted Breakthrough Therapy designation for donanemab based on the results of a phase 2 clinical trial called TRAILBLAZER-ALZ that evaluated the safety and efficacy of donanemab in patients with Alzheimer’s disease. In the trial, 257 patients with early symptomatic Alzheimer’s disease received either donanemab or placebo intravenously every four weeks for up to 72 weeks. Compared with those who received placebo, those who received donanemab experienced less cognitive and functional decline over the course of the trial, as measured by the change from baseline on the Integrated Alzheimer’s Disease Rating Scale.Although the TRAILBLAZER-ALZ trial included more than 100 patients treated with donanemab, due to the speed of plaque reduction, many patients were able to stop dosing as early as six months of treatment, resulting in fewer than 100 patients receiving 12 months of donanemab. FDA Reviews Nasal Nalmefene for Treating Opioid OverdoseThe FDA has accepted for Priority Review a New Drug Application (NDA) for OPNT003 (nasal nalmefene) for the treatment of opioid overdose, Opiant Pharmaceuticals announced in January. Priority Review is granted to therapies that the FDA determines have the potential to provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. OPNT003 was previously granted Breakthrough Therapy designation when a confirmatory pharmacokinetic study comparing a 3 mg spray of the drug with a 1 mg intramuscular nalmefene hydrochloride injection in 68 healthy patients revealed that OPNT003 achieved higher plasma concentrations compared with the intramuscular injection.The NDA also included data from a second study that found similar plasma concentrations of OPNT003 whether the treatment was administered as a single dose in each nostril or as two doses in a single nostril. A third study found the drug to be noninferior to intranasal naloxone and found that nasal nalmefene produced a greater reversal of remifentanil-induced respiratory depression that was nearly twice that produced by nasal naloxone at five minutes. Brexpiprazole Gets Priority Review for Treating Alzheimer’s Agitation In January Otsuka Pharmaceutical Co., Ltd. and H. Lundbeck A/S announced that the FDA has granted Priority Review for its supplemental NDA (sNDA) for brexpiprazole for the treatment of agitation associated with Alzheimer’s dementia.The sNDA submission includes data from two positive clinical phase 3 studies that investigated the treatment of brexpiprazole in patients with agitation related to Alzheimer’s dementia. In Study 331-12-283, 433 patients with agitation associated with Alzheimer’s took either 1 or 2 mg of brexpiprazole or placebo daily for 12 weeks. Those who took 2 mg of brexpiprazole had greater improvements in their Cohen-Mansfield Agitation Inventory (CMAI) Total Score from baseline to week 12 compared with placebo. In Study 331-14-213, which included 345 patients, patients were randomized to either 2 or 3 mg of brexpiprazole or placebo daily for 2 weeks. Those who took either dose of brexpiprazole had greater improvements in their CMAI Total Score from baseline to week 12 compared with placebo. ■ ISSUES NewArchived

Med Check: Alzheimer’s Agitation, Idiopathic Hypersomnia, Depression, and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Alzheimer’s Agitation, Idiopathic Hypersomnia, Depression, and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:4 Jan 2023https://doi.org/10.1176/appi.pn.2023.01.1.5AXS-05 May Delay Relapse of Alzheimer’s AgitationAxsome Therapeutics’ investigational combination drug AXS-05 (45 mg dextromethorphan/105 mg bupropion) may delay relapse of agitation associated with Alzheimer’s disease, the company announced in November.In the phase 3 ACCORD trial, 108 patients with Alzheimer’s disease agitation who had already responded to AXS-05 in a previous, open-label trial either continued treatment with the drug or were switched to placebo for up to 26 weeks. Relapse was defined as a worsening of 10 points or more on the Cohen-Mansfield Agitation Inventory (CMAI) from the time the patients were randomized to either continued treatment or to placebo, a CMAI total score greater than when they entered the study, or hospitalization or other institutionalization because of agitation associated with Alzheimer’s disease.Patients who took AXS-05 had a 3.6-fold lower risk of relapse compared with those who took placebo. During the trial, 7.5% of patients who took the drug experienced a relapse of Alzheimer’s disease agitation, compared with 25.9% of those who took placebo. Serdexmethylphenidate Granted Orphan Drug Status for Idiopathic Hypersomnia The Food and Drug Administration (FDA) has granted orphan drug status to serdexmethylphenidate for the treatment of idiopathic hypersomnia, KemPharm Inc. announced in November. Serdexmethylphenidate is KemPharm’s prodrug of d-methylphenidate.The FDA may grant orphan drug status to investigational therapies that address rare medical diseases or conditions. If the drug later receives FDA approval for treating the disease or condition, the FDA may not approve any other applications to market the same drug for the same indication for seven years, except in limited circumstances.KemPharm will soon begin a phase 2 trial of serdexmethylphenidate in patients with idiopathic hypersomniaand a second trial in patients with narcolepsy.Serdexmethylphenidate is also an active ingredient in Corium’s Azstarys (serdexmethylphenidate and dexmethylphenidate), which the FDA approved in March of 2021 for treating symptoms of attention-deficit/hyperactivity disorder in patients aged 6 years and older. Spravato May Be More Effective Than Quetiapine XR for TRDAn open-label phase 3b trial suggests that Spravato (esketamine nasal spray) may have greater efficacy than quetiapine extended release (XR) for treating symptoms of treatment-resistant depression (TRD) in adults, Janssen Pharmaceutical Companies announced in November. Janssen is the manufacturer of Spravato.In the ESCAPE-TRD trial, 676 patients with TRD were randomized to receive either Spravato or quetiapine XR, both in combination with a continuing selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor, for 32 weeks. At the eighth week, 21.7% of the patients who received Spravato experienced remission of their symptoms, compared with 14.1% of those who took quetiapine. At study’s end, symptoms abated in 55% of patients who took Spravato, compared with 37% of those who took quetiapine FDA to Review IPX203 for Parkinson’s DiseaseIn November, Amneal Pharmaceuticals Inc. announced that the FDA has accepted for review the company’s New Drug Application for IPX203 (carbidopa/levodopa extended release) for the treatment of Parkinson’s disease.In the phase 3 RISE-PD trial, 506 patients who were at least 40 years old when they were diagnosed with Parkinson’s disease were randomized to receive either IPX203 or immediate-release carbidopa/levodopa. All patients had motor fluctuations.The primary endpoint was change from baseline in the daily amount of “Good On” time, defined as the sum of “On” time without dyskinesia and “On” time with non-troublesome dyskinesia. At the twentieth week, those who took IPX203 had an average of roughly half an hour more of “Good On” time compared with those who took immediate-release carbidopa/levodopa.In addition, a study published in the May 2022 Neurology found that 29.7% of patients who took IPX203 were “much improved” or “very much improved,” as evidenced in their scores on the Patient Global Impression of Change, compared with 18.8% of those who took immediate-release carbidopa/levodopa. ■“A Phase 3 Trial of IPX203 vs CD-LD IR in Parkinson’s Disease Patients with Motor Fluctuations (RISE-PD)” ISSUES NewArchived

Efficacy, Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: A 12‐Week, Randomized, Double‐Blind, Placebo‐Controlled Trial

AbstractBackgroundAgitation is a prevalent clinical manifestation of Alzheimer’s dementia, and is one of the most stressful aspects of care in patients affected by the disease. However, currently, there are no FDA‐approved pharmacological treatments for agitation in this patient population. Following two prior clinical trials of brexpiprazole in this patient population, the aim of this study was to confirm the efficacy, safety and tolerability of brexpiprazole in patients with agitation in Alzheimer’s dementia.MethodsThis was a 12‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐arm study (NCT03548584). Eligible patients were aged 55–90 years, in a care facility or community‐based setting, had a diagnosis of probable Alzheimer’s disease, and met criteria for agitation as defined by the International Psychogeriatric Association (IPA). Patients were randomized 2:1 to brexpiprazole or placebo; within the brexpiprazole arm, patients were further randomized 1:2 to fixed‐dose 2 mg/day or 3 mg/day. Stable background medications for the treatment of Alzheimer’s disease were permitted. The primary endpoint was change from baseline to Week 12 in Cohen–Mansfield Agitation Inventory (CMAI) Total score. The key secondary endpoint was change from baseline to Week 12 in Clinical Global Impression − Severity of illness (CGI‐S) score, as related to agitation. Safety was also assessed.ResultsA total of 345 patients were randomized to brexpiprazole or placebo. On the primary endpoint, the mean change from baseline to Week 12 in CMAI Total score was statistically significantly greater in the brexpiprazole group (2 mg/day or 3 mg/day) versus the placebo group (p = 0.0026). Statistically significant separation between the brexpiprazole and placebo groups was also observed on the key secondary endpoint of change from baseline to Week 12 in CGI‐S score (p = 0.0055). Aside from headache (6.6%), no other treatment‐emergent adverse events occurred with an incidence ≥5% in the brexpiprazole group.ConclusionIn this Phase 3 study of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole was associated with a statistically significantly greater reduction in agitation, and improvement in clinical global impression of agitation, compared with placebo, supporting the findings of two prior clinical trials. Brexpiprazole was generally well tolerated, and no new safety signals were observed.

Essential oils for agitation in dementia [rELOAD]: A pragmatic, cluster-randomized, placebo-controlled, pilot feasibility trial

BackgroundClinical guidelines recommend non-pharmacological interventions as the first line of treatment for agitation in dementia. One intervention that shows some promise as a treatment for agitation is essential oils. The objective of this study was to provide preliminary evidence of the effectiveness and feasibility of using topically-administered, individualized essential oil preparations for the alleviation of agitation in persons with dementia. MethodsWe conducted a 10-week pragmatic, cluster-randomized, placebo-controlled, pilot feasibility trial to compare the effectiveness of topically-administered, individualized essential oil preparations to control (placebo) preparations. Outcomes included frequency and severity of agitation, quality of life, frequency of antipsychotic medication use and physical restraint, incidence of adverse events, and trial feasibility. Participants with dementia and clinically significant agitation were recruited from five residential aged-care facilities across regional South Australia. ResultsThirty-eight participants were randomized from five sites. Accounting for random effects, we found statistically significant differences between the intervention and control groups in Pittsburgh Agitation Scale (PAS) aberrant vocalization sub score, Cohen Mansfield Agitation Inventory (CMAI) verbally agitated sub score and CMAI total score at week 4, but not at weeks 8 (post-intervention) or 10 (follow-up). No significant time-group interactions were observed for other PAS/CMAI scores or sub scores, quality of life - Alzheimer's disease total score, or frequency of physical restraint or as-needed antipsychotic medication. No adverse events were reported in any group. ConclusionsThe study findings highlight some promising effects of topically-administered, individualized essential oil preparations for agitation in dementia, and indicate that a large multi-center, cluster-randomized controlled trial of this treatment is feasible. Trial registrationAustralian New Zealand Clinical Trial Registry [ACTRN12617001159347].

Efficacy and safety of AXS‐05, a novel oral NMDA receptor antagonist with multimodal activity in agitation associated with Alzheimer’s disease: Results from ADVANCE‐1 — A phase 2/3, double‐blind, active and placebo‐controlled trial

AbstractBackgroundAXS‐05 (dextromethorphan/bupropion modulated delivery tablet) is a novel, oral, non‐competitive NMDA receptor antagonist with activity on other neurotransmitter systems (sigma‐1, serotonin, norepinephrine, and dopamine) which have been implicated in the cognitive and behavioral abnormalities of Alzheimer’s disease (AD). Up to 70% of patients with AD experience agitation. AD agitation is associated with accelerated cognitive decline, early institutionalization, increased mortality, and increased caregiver burden. There are no approved pharmacological treatments for AD agitation.MethodThe ADVANCE‐1 trial was a Phase 2/3, randomized, double‐blind, controlled, 5‐week study of AXS‐05 in AD agitation. Patients were randomized to treatment with AXS‐05, placebo, or bupropion. The primary endpoint was the change from baseline in the Cohen Mansfield Agitation Inventory (CMAI). The modified Alzheimer’s Disease Cooperative Study‐Clinical Global Impression of Change for Agitation (mADCS‐CGIC) was a key secondary endpoint.Result366 AD patients with clinically significant agitation were randomized to AXS‐05 (n=159), bupropion (n=49), and placebo (n=158). On the primary endpoint, AXS‐05 significantly relieved agitation, demonstrating a change from baseline in the CMAI total score of 15.4 compared to 11.5 for placebo (p=0.010) and 10.0 for bupropion (p&lt;0.001). These results represent a mean percentage reduction from baseline of 48% for AXS‐05 versus 38% for placebo. AXS‐05 was numerically superior to placebo starting at Week 2, achieving statistical significance at Week 3 (p=0.007) only one week after full dosing with AXS‐05. AXS‐05 demonstrated clinical response (≥30% improvement on the CMAI) in 73% of patients compared to 57% for placebo (p=0.005). AXS‐05 demonstrated statistically significant improvements in agitation as compared to placebo on the mADCS‐CGIC (p=0.036). The most commonly reported AEs with AXS‐05 were somnolence (8.2% AXS‐05, 4.1% bupropion, 3.2% placebo), dizziness (6.3%, 10.2%, 3.2%, respectively), and diarrhea (4.4%, 6.1%, 4.4%, respectively). There was no evidence of cognitive decline or sedation with AXS‐05.ConclusionIn the ADVANCE‐1 Phase 2/3 trial, AXS‐05 rapidly, substantially, and significantly improved agitation in patients with AD as compared to placebo. AXS‐05 was well tolerated and not associated with cognitive decline or sedation.

The Prevalence and Determinants of Neuropsychiatric Symptoms in People With Acquired Brain Injury in Nursing Homes

ObjectivesEstablishing the prevalence and determinants of neuropsychiatric symptoms (NPS) in patients with acquired brain injury (ABI) in nursing homes. DesignCross-sectional, observational study. Setting and ParticipantsPatients 18-65 years old with ABI in special care units in Dutch nursing homes. MethodsNursing homes were recruited through the national expertise network for patients with severe ABI, regional brain injury teams, and by searching the Internet. Patient characteristics were collected through digital questionnaires. NPS were assessed with the Neuropsychiatric Inventory-Nursing Home version (NPI-NH) and the Cohen-Mansfield Agitation Inventory (CMAI), cognition with the Mini-Mental State Examination, and activities of daily living with the Disability Rating Scale. Psychotropic drug use (PDU) was retrieved from the electronic prescription system. Individual NPS were clustered. Associations between determinants and NPS were examined using multilevel multivariate linear regression models. ResultsIn a population of 118 patients from 12 nursing homes, 73.7% had 1 or more clinically relevant NPS and 81.3% 1 or more agitated behaviors. The most common NPS were agitation, in particular aberrant motor behavior (24.6%), repetitious sentences/questions (35.5%), and constant requests for attention (34.6%), verbal (33.6%) and physical (50.5%) aggression, and irritability (28.0%). Male patients were more likely to display hyperactivity. Being married was associated with less verbally agitated behavior and pain was associated with a higher CMAI total score. PDU increased the likelihood of a higher NPI-NH total score. Conclusions and ImplicationsNPS are common in patients with ABI ≤65 years of age residing in nursing homes. This is a first step to fill in the knowledge gap concerning NPS in this population. An increasing number of patients with severe ABI may survive the acute phase and will reside many years in nursing homes. It is important to shed more light on these NPS, with regard to course, magnitude, and severity, to ultimately develop appropriate care for this vulnerable group of patients.

Healthcare resource utilisation and costs of agitation in people with dementia living in care homes in England - The Managing Agitation and Raising QUality of LifE in Dementia (MARQUE) study.

BackgroundPeople with dementia living in care homes often experience clinically significant agitation; however, little is known about its economic impact.ObjectiveTo calculate the cost of agitation in people with dementia living in care homes.MethodsWe used the baseline data from 1,424 residents with dementia living in care homes (part of Managing Agitation and Raising QUality of lifE in dementia (MARQUE) study) that had Cohen-Mansfield Agitation Inventory (CMAI) scores recorded. We investigated the relationship between residents’ health and social care costs and severity of agitation based on the CMAI total score. In addition, we assessed resource utilisation and compared costs of residents with and without clinically significant symptoms of agitation using the CMAI over and above the cost of the care home.ResultsAgitation defined by the CMAI was a significant predictor of costs. On average, a one-point increase in the CMAI will lead to a 0.5 percentage points (cost ratio 1.005, 95%CI 1.001 to 1.010) increase in the annual costs. The excess annual cost associated with agitation per resident with dementia was £1,125.35. This suggests that, on average, agitation accounts for 44% of the annual health and social care costs of dementia in people living in care homes.ConclusionAgitation in people with dementia living in care homes contributes significantly to the overall costs increasing as the level of agitation increases. Residents with the highest level of agitation cost nearly twice as much as those with the lowest levels of agitation, suggesting that effective strategies to reduce agitation are likely to be cost-effective in this setting.

Nursing Home Residents with Dementia and Very Frequent Agitation: A Particular Group

Although many nursing home residents with dementia show agitation, hardly any literature is published about very frequent agitation. The WAALBED-III study focuses on the 2-week prevalence and correlates of very frequent agitation in these residents. Cross-sectional study using combined data of four studies. One hundred nineteen dementia special care units in twenty-six nursing homes in The Netherlands. Two thousand seventy-four residents with dementia. We operationally defined very frequent agitation as having a score of 6 (several times a day) or 7 (several times an hour) on at least five items of the Cohen Mansfield Agitation Inventory (CMAI) combined with a CMAI total score above the 90th percentile. To assess the association of demographic and behavioral characteristics with very frequent agitation, we performed a multivariate multilevel logistic regression analysis. The 2-week prevalence of very frequent agitation was 7.4% (95% CI: 6.374-8.634). Correlates for very frequent agitation were age (OR: 0.967, 95% CI: 0.942-0.992), dementia severity (GDS 6 = OR: 3.636, 95% CI: 1.929-6.875; GDS 7 = OR: 2.951, 95% CI: 1.321-6.588), delusions (OR: 2.480, 95% CI: 1.555-3.956), anxiety (OR: 1.904, 95% CI: 1.259-2.881), euphoria (OR: 3.712, 95% CI: 2.171-6.337) and irritability (OR: 4.411, 95% CI: 2.854-6.816). To our knowledge, this study is the first to report prevalence data and correlates about nursing home residents with very frequent agitation. We found several correlated factors for very frequent agitation. Still, further research is needed for a better understanding of the behavior of this group, and to identify good treatment options.

Prevalence and associated behavioral symptoms of depression in mild cognitive impairment and dementia due to Alzheimer's disease

Mild cognitive impairment (MCI) is a clinical concept that categorizes subjects who are in an intermediate cognitive state between normal aging and dementia. The aims of this study are to determine the prevalence of significant depressive symptoms in MCI and Alzheimer's disease (AD) patients and to characterize the behavior associated with significant depressive symptoms in MCI and AD patients. A cross-sectional analysis of baseline data from a prospective, longitudinal study on behavioral symptoms of dementia and MCI was performed. The study population consisted of 270 MCI and 402 AD patients. Behavioral assessment was performed by means of Middelheim Frontality Score, Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) and Cohen-Mansfield Agitation Inventory. The presence of significant depressive symptoms was defined as a Cornell Scale for Depression in Dementia total score >7. The prevalence of significant depressive symptoms in AD patients (25%) was higher compared with MCI patients (16%) (p = 0.005). Patients with significant depressive symptoms showed an increased severity of frontal lobe symptoms, behavioral symptoms and agitation (Middelheim Frontality Score, Behave-AD and Cohen-Mansfield Agitation Inventory total scores; p < 0.001). Also, most of the individual frontal lobe and behavioral symptoms were more prevalent and severe, resulting in higher Behave-AD global scores. Mild cognitive impairment patients with depressive symptoms showed more severe behavioral symptoms and more severe verbally agitated behavior than AD patients without depressive symptoms (p < 0.001). Frontal lobe and behavioral symptoms are more prevalent and severe in MCI and AD patients with significant depressive symptoms as compared with patients without depressive symptoms.

Antidepressants for agitation and psychosis in dementia

Agitation and psychosis are common among older adults with dementia and are challenging to manage. At the present time, little is known about the efficacy and safety of antidepressant medications when used to treat these symptoms. To assess the safety and efficacy of antidepressants in treating psychosis and agitation in older adults with Alzheimer's disease, vascular, or mixed dementia. We searched the Cochrane Dementia and Cognitive Improvement Group's Specialized Register which included Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 3), MEDLINE (January 1950 to October 2009), EMBASE (1980 - October 2009), CINAHL (all dates - October 2009) and PsycINFO (1806 to October 2009). Randomized, controlled trials of antidepressants (selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, trazodone, and other antidepressants), compared to either placebo or comparator medications (typical or atypical antipsychotics, anticonvulsants, benzodiazepines, cholinesterase inhibitors, memantine or other medications) for treatment of agitation or psychosis in older adults with dementia. Two authors independently assessed trial quality and extracted trial data. We collected information on efficacy as measured by dementia neuropsychiatric symptom rating scales and adverse effects. Study authors were contacted for additional information. Nine trials including a total of 692 individuals were included in the review. Five studies compared SSRIs to placebo and two studies were combined in a meta-analysis for the outcome of change in Cohen-Mansfield Agitation Inventory (CMAI) scores. There was a significant difference between antidepressants and placebo on measures of agitation as reported on the change in CMAI total score (mean difference (MD), -0.89, 95% CI, -1.22 to -0.57) although the results were heavily weighted by one large study. There were no significant differences in change in behavioral symptoms of dementia for SSRIs compared to placebo in the one study that reported on changes in the Neuropsychiatric Inventory and Behavioral Pathology in Dementia scales. One study comparing citalopram to placebo found a significant difference in NPS as measured on the Neurobehavioral Rating Scale (NBRS) after controlling for baseline severity NBRS score although the unadjusted mean difference was not statistically significant (MD - 7.70, 95% CI: -16.57 to 1.17). There was no difference in the rates of trial withdrawals due to adverse events for SSRIs compared to placebo for four studies reporting this outcome (relative risk (RR), 1.07, 95% CI: 0.55 to 2.11) or in the number of trial withdrawals due to any cause in the three studies reporting this outcome (RR, 0.91, 95% CI, 0.65 to 1.26). One study compared the SSRI citalopram to the atypical antipsychotic risperidone and found no difference in NBRS scores, trial withdrawals due to any cause or trial withdrawals due to adverse events although the rates of adverse events as measured on the UKU side effect scale total score were lower for citalopram (MD -2.82, 95% CI: -4.94 to -0.70). Three studies compared SSRIs to typical antipsychotics. In meta-analysis of two studies there was no statistically significant differences in changes in CMAI total scores (MD, 4.66, 95% CI: -3.58 to 12.90). There was also no difference in trial withdrawals due to any cause or due to adverse events for SSRIs compared to typical antipsychotics. One study of trazodone compared to placebo did not find any significant difference in change in CMAI total scores (MD, 5.18, 95% CI, -2.86 to 13.22) or trial withdrawals due to any cause (RR, 1.06, 95% CI, 0.54 to 2.09). Two studies comparing trazodone to haloperidol also failed to detect any difference in change in CMAI total scores (MD, 3.28, 95% CI, -3.28 to 9.85) or trial withdrawals due to any cause (RR, 0.79, 95% CI, 0.43 to 1.46). Currently there are relatively few studies of antidepressants for the treatment of agitation and psychosis in dementia. The SSRIs sertraline and citalopram were associated with a reduction in symptoms of agitation when compared to placebo in two studies. Both SSRIs and trazodone appear to be tolerated reasonably well when compared to placebo, typical antipsychotics and atypical antipsychotics. Future studies involving more subjects are required to determine if SSRIs, trazodone, or other antidepressants are safe and effective treatments for agitation and psychosis in dementia.

Assessing neuropsychiatric symptoms in nursing home patients with dementia: reliability and Reliable Change Index of the Neuropsychiatric Inventory and the Cohen-Mansfield Agitation Inventory

The aim of the study was to estimate inter-observer and test-retest reliability of the Neuropsychiatric Inventory Nursing Home version (NPI-NH) and the Cohen-Mansfield Agitation Inventory (CMAI), and to establish their Reliable Change Index (RCI). Reliable Change methodology is a practical method for estimating the least change acquired in outcome measures. Nursing home physicians and certified nurses assessed 105 patients with dementia (in five nursing homes) at baseline and after 2 weeks. Spearman rank correlations were calculated and Reliable Change Difference Scores (S(diff) (80)). NPI-NH inter-observer correlations ranged 0.14-0.70. NPI-NH test-retest correlations ranged 0.23-0.80. CMAI inter-observer correlations ranged -0.10 to 0.72. CMAI test-retest correlations ranged 0.32-1.00 (CMAI total score, ρ=0.89). S(diff) (80) for NPI-NH items ranged 1.7-5.0. A change of 11 points on the NPI-NH total score can be considered a true behavioral change. S(diff) (80) for CMAI total score was 8 and factor analysis based sub-scale scores physically aggressive behavior, physically non-aggressive behavior, and verbally agitated behavior were 3, 6, and 4, respectively. Reliability estimates and RCI for the NPI-NH were modest, seriously challenging its reliability and sensitivity to change over time. NPI-NH may only be useful for monitoring behavioral changes in individual patients with dementia, when symptoms are moderate to severe, or when effect sizes are large. Reliability of the CMAI was good, supporting its usefulness in clinical practice. Poor inter-observer agreement on behavioral observations poses a real challenge in nursing homes. Reliable scales are needed that include unambiguously formulated items.

P4-176: Actigraphic measurement of agitated behavior in dementia

Actigraphic recordings have already been used to detect activity–rest disturbances in dementia and seem a promising tool to study agitation in a standardized fashion. As actigraphy has not yet been validated as a measure of agitation in dementia, we examined the correlation between actigraphic measures and a validated assessment scale of agitated behavior in dementia, the Cohen–Mansfield Agitation Inventory (CMAI). Diagnosed according to strictly applied clinical diagnostic criteria, patients with Alzheimer's disease (AD; n=65), mixed dementia (MXD; n=20), frontotemporal dementia (FTD; n=9) and dementia with Lewy bodies (DLB; n=16) were included in the study (total n=110). All patients underwent actigraphic recordings for 48 hours. CMAI was scored by professional caretakers, who were responsible for the patient during his or her actigraphic recording. Mean age of the patients included was 78±8 years. Average MMSE was 15.1±6.8. Patients with high total CMAI scores (≥50) clearly had higher levels of activity during the day as measured by means of actigraphy than patients with low total CMAI scores (ANOVA, F=126.75, p<0.0001). Patients with low MMSE scores (<20) also had higher activity levels during the day than patients with higher MMSE scores (ANOVA, F=85.74, p<0.0001). Correlations between actigraphic data and CMAI total scores were moderate but highly significant. We conclude that actigraphy is a useful tool to examine agitated behavior in dementia.

Actigraphic measurement of agitated behaviour in dementia

This study examines the correlation between actigraphic measures and a validated assessment scale of agitated behaviour in dementia, the Cohen-Mansfield Agitation Inventory (CMAI). A total of 110 patients were included. Patients either suffered from Alzheimer dementia (AD), mixed dementia (MXD), frontotemporal dementia (FTD) or diffuse Lewy body disease (DLB). All patients underwent actigraphic recordings for 48 h. CMAI was scored by professional caretakers, who were responsible for the patient during his or her actigraphic recording. Patients with high total CMAI scores (>or= 50) clearly had higher levels of activity during the day as measured by means of actigraphy than patients with low total CMAI scores (ANOVA, F=126.75, p<0.0001). Patients with low MMSE scores (<20) also had higher activity levels during the day than patients with higher MMSE scores (ANOVA, F= 85.74, p<0.0001). Correlations between ctigraphic data and CMAI total scores were moderate but highly significant. We conclude that actigraphy is a useful tool to examine agitated behaviour in dementia.

Management of agitation, aggression, and psychosis associated with dementia: A pooled analysis including three randomized, placebo-controlled double-blind trials in nursing home residents treated with risperidone

This analysis used pooled data from three randomized, placebo-controlled trials that examined the efficacy and safety of risperidone for the treatment of agitation, aggression, and psychosis associated with dementia in elderly nursing home residents to assess the risk-benefit of the use of risperidone in this population. The efficacy data (risperidone n = 722, placebo n = 428) were obtained from the Cohen-Mansfield agitation inventory (CMAI) and behavioral pathology in Alzheimer's disease (BEHAVE-AD) total and subscales. Additionally, clinical global impression (CGI) assessments were performed. Subgroup analyses were performed by type of dementia, severity of dementia, presence or absence of somnolence as an adverse event, and presence or absence of psychosis at baseline. Safety assessments included evaluation of treatment emergent adverse events, Extrapyramidal Symptom Rating Scale, ECG and vital signs, and Mini-Mental State Examination (MMSE). The mean dose of risperidone at end point was 1.0 mg/day (0.02 S.E.). The observed mean change at end point was significantly higher for risperidone than for placebo on CMAI total score (−11.8 versus −6.4, respectively; p < 0.001), total aggression score (−5.0 versus −1.8, respectively; p < 0.001), BEHAVE-AD total score (−6.1 and −3.6, respectively; p < 0.001), and psychotic symptoms score (−2.1 and −1.3, respectively; p = 0.003). The main treatment effects of risperidone were similar in all subgroup analyses. Additionally, risperidone-treated patients scored significantly better than placebo-treated patients on the CGI scales at end point. The incidence of treatment-emergent adverse events was comparable between risperidone (84.3%) and placebo (83.9%). More patients discontinued due to adverse events in the risperidone-treated group (17.2%) than in the placebo group (11.2%). Differences in adverse event incidences between placebo and risperidone were observed for extrapyramidal symptoms (EPS), mild somnolence and the less common cerebrovascular adverse events (CAE). Risperidone induced neither orthostatic, nor anticholinergic side effects nor falls nor cognitive decline. Of all atypical antipsychotics, risperidone has the largest database of double-blind controlled trials to support its efficacy and safety in the treatment of agitation, aggression, and psychosis associated with dementia. At the recommended doses, risperidone displayed a favorable risk-benefit profile. Risperidone was well tolerated with respect to EPS, somnolence, and anticholinergic side effects in this elderly population. In view of the risk for CAEs, risperidone, should be targeted towards the treatment of those patients in whom psychotic and behavioral symptoms of dementia are prominent and associated with significant distress, functional impairment or danger to the patient.

Components of behavioral pathology in dementia

The purpose of this study was to examine the occurence of the noncognitive behavioral and psychological symptoms and signs of dementia in a geriatric chronic-care hospital and to separate agitated and affective components of behavioral pathology using factor analysis. The frequency and severity of Alzheimer's disease, vascular dementia, mixed dementia and Lewy Body dementia was assessed in 145 consecutive residents of a chronic-care hospital. The presence of noncognitive behavioral symptoms was evaluated with the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and the Cohen-Mansfield Agitation Inventory (CMAI). A Factor analysis on the BEHAVE-AD subscores was performed to create symptom clusters. Analysis of covariance and post hoc tests were used to compare means of factor variables between different types of dementia. Statistical analysis showed a significant correlation between severity of dementia and BEHAVE-AD total score and between severity of dementia and CMAI total score. Factor analysis with Varimax rotation revealed the presence of three behavioral subsyndromes: agitation, affectivity and day/night disturbances. The finding of three factors of behavioral pathology in demented patients reflects the possibility that different etiological mechanisms could explain the expression of the symptoms and signs of psychosis in demented patients.

Quetiapine Treatment for Behavioral and Psychological Symptoms in Patients with Senile Dementia of Alzheimer Type

The purpose of this study was to assess the effect of quetiapine in the treatment of behavioral and psychological symptoms of dementia (BPSD) in patients with senile dementia of Alzheimer type (SDAT). Sixteen SDAT patients with BPSD were recruited and quetiapine (25– 200 mg/day) was prescribed for 8 weeks. BPSD were evaluated with the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) and Cohen-Mansfield Agitation Inventory (CMAI) at week 0 (baseline) and week 8 (endpoint). The severity of the extrapyramidal symptoms was also assessed by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) at baseline and endpoint. Significant improvements were seen in the CMAI total score and in the BEHAVE-AD subscales of delusions, activity disturbances, aggressiveness, diurnal rhythm disturbances and in the BEHAVE-AD overall severity. There was no significant difference between the baseline and endpoint in the DIEPSS score. These data indicate that quetiapine is effective in controlling BPSD with favorable adverse-event profiles.