Speed of Improvement in Symptoms of Depression With Desvenlafaxine 50 mg and 100 mg Compared With Placebo in Patients With Major Depressive Disorder.

PURPOSE/BACKGROUND: This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus placebo. METHODS: Data were pooled from 9 short-term, double-blind, placebo-controlled studies in adults with MDD randomly assigned to desvenlafaxine 50 mg/d, 100 mg/d, or placebo. A mixed-effects model for repeated-measures analysis of change from baseline score was used to determine the time point at which desvenlafaxine treatment groups separated from placebo on the 17-item Hamilton Rating Scale for Depression and psychosocial outcomes. The association between early improvement and week 8 outcomes was examined using logistic regression analyses. Time to remission for patients with early improvement versus without early improvement was assessed using Kaplan-Meier techniques. Comparisons between groups were performed with log-rank tests. RESULTS: In the intent-to-treat population (N = 4279 patients: desvenlafaxine 50 mg/d, n = 1714; desvenlafaxine 100 mg/d, n = 870; placebo, n = 1695), a statistically significant improvement on the 17-item Hamilton Rating Scale for Depression was observed with desvenlafaxine 50 mg/d at week 1 (P = 0.0129) and with desvenlafaxine 100 mg/d at week 2 (P = 0.0002) versus placebo. Early improvement was a significant predictor of later remission. Treatment assignment, baseline depression scale scores, and race were significantly associated with probability of early improvement. On several measures of depressive symptoms and function, desvenlafaxine 50 mg/d and 100 mg/d separated from placebo as early as week 1 and no later than week 4 in patients with MDD. IMPLICATIONS/CONCLUSIONS: These findings suggest that clinicians may be able to use depression rating scale scores early in treatment as a guide to inform treatment optimization.

Effect of desvenlafaxine 50 mg and 100 mg on energy and lassitude in patients with major depressive disorder: A pooled analysis.

Nine randomized, double-blind, placebo-controlled studies of major depressive disorder were pooled to evaluate the effects of desvenlafaxine 50- and 100-mg/d on energy and lassitude in adults with major depressive disorder ( n=4279). Changes from baseline to endpoint in 17-item Hamilton Rating Scale for Depression (HAM-D17) Work and Activities, Retardation, and Somatic Symptoms General items, HAM-D17 psychomotor retardation factor, and Montgomery-Åsberg Depression Rating Scale Lassitude item were analyzed with a mixed model for repeated measures analysis of variance. Associations between residual energy measures and functional impairment, based on the Sheehan Disability Scale, were modeled using stepwise multiple linear regression. Improvement from baseline was significantly greater for both desvenlafaxine doses versus placebo on all energy symptom outcomes at week 8 (all p⩽0.005). Both early improvement in HAM-D17 psychomotor retardation at week 2 and residual energy symptoms at week 8 were associated with Sheehan Disability Scale total score at week 8 (all p⩽0.001). Among Sheehan Disability Scale remitters and responders, the HAM-D17 psychomotor retardation score at week 8 was significantly lower with desvenlafaxine (both doses) than placebo. Desvenlafaxine 50 and 100 mg/d significantly improved energy and lassitude symptoms in patients with major depressive disorder. Both early improvement in energy and fewer residual energy symptoms were associated with functional improvement.

An integrated analysis of the efficacy and safety of desvenlafaxine in the treatment of major depressive disorder.

The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of antidepressant pharmacotherapy as the presence of residual depressive symptoms is associated with an increased risk of relapse. Treatment guidelines recommend selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or atypical antidepressants as first-line treatment for moderate to severe MDD. Desvenlafaxine, administered as desvenlafaxine succinate, is an serotonin-norepinephrine reuptake inhibitor approved for the treatment of adults with MDD at the recommended dose of 50 mg/day. The aim of this integrated analysis was to assess the efficacy and safety of desvenlafaxine 50 and 100 mg/day compared with placebo in adult outpatients with MDD. The analysis used data from nine fixed-dose, short-term, placebo-controlled studies in adult outpatients diagnosed with MDD who had depressive symptoms for at least 30 days. Data from 4279 and 4317 patients were pooled for the efficacy and safety analyses, respectively. Statistically significant improvements were observed with desvenlafaxine 50 and 100 mg/day versus placebo for all efficacy endpoints assessed, including improvements in depressive symptoms, response and remission rates, as well as functional and cognitive outcomes. Treatment with desvenlafaxine 50 and 100 mg/day was generally safe and well tolerated. The findings of this integrated analysis of data from a large population of patients with MDD confirmed the antidepressant efficacy of both desvenlafaxine doses and add to previous evidence supporting the efficacy of desvenlafaxine.

Effect of metabolic syndrome and thyroid hormone on efficacy of desvenlafaxine 50 and 100 mg/d in major depressive disorder.

OBJECTIVE: This pooled, post hoc analysis evaluated the efficacy of desvenlafaxine vs placebo in adults with major depressive disorder (MDD) with and without metabolic syndrome, and above or at or below median baseline thyroid-stimulating hormone (TSH) levels. RESEARCH DESIGN AND METHODS: Patients were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo in nine short-term, double-blind studies. Metabolic syndrome was defined as meeting at least three of five criteria based on body mass index, triglycerides, high-density lipoprotein, fasting glucose, blood pressure, current medication, and medical history. CLINICAL TRIAL REGISTRATION: NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457. MAIN OUTCOME MEASURES: Treatment effects on change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at week 8 (last observation carried forward [LOCF]) were analyzed in four subgroups-metabolic syndrome and no metabolic syndrome, baseline TSH levels above median or at or below median-using analysis of covariance with treatment, study, and baseline in the model. Metabolic syndrome and TSH were examined as predictors of change in HAM-D17 total score using regression analysis. RESULTS: The pooled analysis included 4279 patients; 971 (22.7%) patients had metabolic syndrome. In all subgroups, HAM-D17 total scores improved significantly from baseline to week 8 (LOCF) with desvenlafaxine 50 or 100 mg/d compared with placebo (all p ≤ 0.006). There was no significant treatment by metabolic syndrome or by TSH interaction. Neither metabolic syndrome nor TSH above median predicted change in HAM-D17 total scores, response (≥50% reduction in HAM-D17 total score), or remission (HAM-D17 total score ≤7; all p > 0.05). LIMITATIONS: Individual studies included in this analysis were not designed to examine the relationship between metabolic syndrome or TSH and response to desvenlafaxine treatment. Metabolic syndrome status was determined post hoc based on available baseline measures and not diagnosed at study entry. Exclusion criteria were selected to enroll medically healthy patients with a primary diagnosis of MDD (i.e., patients healthier than the general MDD population). CONCLUSIONS: Desvenlafaxine 50 and 100 mg/d significantly improved depression compared with placebo in patients with and without metabolic syndrome, and in patients with baseline TSH above median and at or below median levels.

Evaluating the cognitive effects of donepezil 23 mg/d in moderate and severe Alzheimer's disease: analysis of effects of baseline features on treatment response.

BACKGROUND: Treatment of Alzheimer's disease with acetylcholinesterase inhibitors can result in symptomatic benefits, but patients often show variable responses. The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23 mg/d or 10 mg/d and to identify factors potentially influencing response. METHODS: A post hoc analysis was conducted using data from a large, 24-week, randomized, double-blind, international study enrolling patients with moderate to severe Alzheimer's disease (baseline Mini-Mental State Examination [MMSE], 0-20) (NCT 00478205). Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24. Univariate and multivariate analyses were also performed. RESULTS: Donepezil 23 mg/d provided statistically significant incremental cognitive benefits over donepezil 10 mg/d irrespective of baseline functional severity, measured by scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living-severe version (P < 0.05). When patients were categorized by baseline cognitive severity (MMSE score), significant benefits of donepezil 23 mg/d over 10 mg/d were seen in both subgroups when based on MMSE scores of 0-9 versus 10-20 (P < 0.02 and P < 0.01, respectively), and in the more severe subgroup when based on MMSE scores of 0-16 versus 17-20 (P < 0.0001 and P > 0.05). Statistically significant incremental cognitive benefits of donepezil 23 mg/d over 10 mg/d were also observed regardless of age, gender, weight, or prestudy donepezil 10 mg/d treatment duration (P < 0.05). In the multivariate analysis, the only significant interaction was between treatment and baseline MMSE score. CONCLUSIONS: The cognitive benefits of donepezil 23 mg/d over 10 mg/d were achieved regardless of the patient's age, gender, weight, duration of prior donepezil 10 mg/d, and functional severity. The influence of baseline cognitive severity on response seemed to be dependent on the level of impairment, with cognitive benefits of donepezil 23 mg/d over 10 mg/d most apparent in those patients at a more advanced stage of disease. These data may be useful in helping practicing physicians make informed decisions for their patients with advanced Alzheimer's disease.

Effects of donepezil 23 mg on Severe Impairment Battery domains in patients with moderate to severe Alzheimer's disease: evaluating the impact of baseline severity.

INTRODUCTION: The US Food and Drug Administration approved a 23 mg daily dose of donepezil for treatment of moderate to severe Alzheimer's disease (AD) based on outcomes from a large trial comparing the 23 mg/day dose with the standard 10 mg/day dose. Results from this study indicated that after 24 weeks, donepezil 23 mg/day provided significant cognitive benefits over donepezil 10 mg/day, measured using the Severe Impairment Battery (SIB). In the analyses reported herein, we further characterize the range of cognitive domains impacted by treatment with donepezil 23 mg/day. METHODS: A post hoc analysis was conducted using data from a 24-week, randomized, double-blind trial comparing donepezil 23 mg/day versus 10 mg/day in 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20). Changes from baseline to week 24 in the nine SIB domain scores were analyzed in the intent-to-treat (ITT) population (baseline MMSE 0 to 20), in patients with more severe baseline AD (MMSE 0 to 16), and in severity strata based on baseline MMSE scores (0 to 5, 6 to 10, 11 to 15, 16 to 20). RESULTS: In the ITT population, changes in six of the nine SIB domains favored donepezil 23 mg/day over donepezil 10 mg/day. LS mean treatment differences were significant for the language, visuospatial ability, and construction domains. In the more advanced cohort of patients (MMSE 0 to 16 at baseline), LS mean treatment differences were statistically significant favoring donepezil 23 mg/day in five of the nine domains: language, memory, visuospatial ability, attention, and construction. Descriptive analysis of LS mean changes in SIB domain scores in the four baseline severity strata showed variable patterns of response; overall, cognitive benefits of donepezil 23 mg/day were greatest in patients with MMSE scores of 0 to 15. CONCLUSIONS: These results suggest that donepezil 23 mg/day provides benefits over 10 mg/day across a range of cognitive domains. The magnitude of benefit and domains impacted varied depending on the stage of AD; significant benefits with higher dose donepezil were most apparent at more advanced stages of AD and were most prominent in the language domain.

Subgroup analysis of US and non-US patients in a global study of high-dose donepezil (23 mg) in moderate and severe Alzheimer's disease.

To better understand responses in the large number of US-based patients included in a global trial of donepezil 23 mg/d versus 10 mg/d for moderate-to-severe Alzheimer's disease (AD), post hoc exploratory analyses were performed to assess the efficacy and safety in US and non-US (rest of the world [RoW]) patient subgroups. In both subgroups, donepezil 23 mg/d was associated with significantly greater cognitive benefits than donepezil 10 mg/d. Significant global function benefits of donepezil 23 mg/d over 10 mg/d were also observed in the US subgroup only. Compared with RoW patients, US patients had relatively more severe AD, had been treated with donepezil 10 mg/d for longer periods prior to the start of the study, and a higher proportion took concomitant memantine. In both subgroups, donepezil had acceptable tolerability; overall incidence of treatment-emergent adverse events was higher in patients receiving donepezil 23 mg/d compared with donepezil 10 mg/d.

Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer's disease.

BACKGROUND: Donepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer's disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD. METHODS: Patients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs. RESULTS: 915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ± 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs.Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study. CONCLUSION: This study shows that long-term treatment with donepezil 23 mg/day is associated with no new safety signals. The elevated incidence of AEs in patients increasing the dose of donepezil from 10 mg/day to 23 mg/day was limited to the initial weeks of the study.

Efficacy and safety of donepezil 23 mg versus donepezil 10 mg for moderate-to-severe Alzheimer's disease: a subgroup analysis in patients already taking or not taking concomitant memantine.

BACKGROUND/AIMS: A large multicenter trial of donepezil 23 mg/day versus donepezil 10 mg/day for moderate-to-severe Alzheimer's disease allowed patients taking concomitant memantine. We evaluated the efficacy/safety of donepezil 23 and 10 mg/day in this trial, with respect to concomitant memantine use. METHODS: Prespecified analysis of data from a 24-week, randomized, double-blind trial. Patients were randomized to donepezil doses (23 vs. 10 mg/day) and stratified by concomitant memantine use (yes or no). Efficacy and safety were assessed for each donepezil dose in subgroups taking or not taking concomitant memantine. RESULTS: At week 24, donepezil 23 mg/day provided significant cognitive benefits over 10 mg/day (p < 0.01) on the Severe Impairment Battery, with or without concomitant memantine (ANCOVA adjusted for baseline score, country and treatment). The higher dose showed no benefit on the global function, Mini-Mental State Examination or activities of daily living measures in either memantine subgroup. Rates of treatment-emergent adverse events (AEs) were higher for donepezil 23 mg/day with memantine (80.7%) than 23 mg/day without memantine (69.7%) or 10 mg/day with/without memantine (66.7/62.0%); across all treatment groups, most events were mild/moderate in severity. Individual rates of serious AEs were low (<1.0%), regardless of concomitant memantine use. CONCLUSION: In this population, concomitant memantine use did not alter the response profile of donepezil 23 vs. 10 mg/day. Donepezil 23 mg was generally safe and well tolerated among patients receiving donepezil alone and among patients receiving a combination of donepezil and memantine therapy.

Collaborative research between academia and industry using a large clinical trial database: a case study in Alzheimer's disease.

BACKGROUND: Large clinical trials databases, developed over the course of a comprehensive clinical trial programme, represent an invaluable resource for clinical researchers. Data mining projects sponsored by industry that use these databases, however, are often not viewed favourably in the academic medical community because of concerns that commercial, rather than scientific, goals are the primary purpose of such endeavours. Thus, there are few examples of sustained collaboration between leading academic clinical researchers and industry professionals in a large-scale data mining project. We present here a successful example of this type of collaboration in the field of dementia. METHODS: The Donepezil Data Repository comprised 18 randomised, controlled trials conducted between 1991 and 2005. The project team at Pfizer determined that the data mining process should be guided by a diverse group of leading Alzheimer's disease clinical researchers called the "Expert Working Group." After development of a list of potential faculty members, invitations were extended and a group of seven members was assembled. The Working Group met regularly with Eisai/Pfizer clinicians and statisticians to discuss the data, identify issues that were currently of interest in the academic and clinical communities that might lend themselves to investigation using these data, and note gaps in understanding or knowledge of Alzheimer's disease that these data could address. Leadership was provided by the Pfizer Clinical Development team leader; Working Group members rotated responsibility for being lead and co-lead for each investigation and resultant publication. RESULTS: Six manuscripts, each published in a leading subspecialty journal, resulted from the group's work. Another project resulted in poster presentations at international congresses and two were cancelled due to resource constraints. CONCLUSIONS: The experience represents a particular approach to optimising the value of data mining of large clinical trial databases for the combined purpose of furthering clinical research and improving patient care. Fruitful collaboration between industry and academia was fostered while the donepezil data repository was used to advance clinical and scientific knowledge. The Expert Working Group approach warrants consideration as a blueprint for conducting similar research ventures in the future.

Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease.

INTRODUCTION: Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function. METHODS: In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated. RESULTS: At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores. CONCLUSIONS: Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.ClinicalTrials.gov identifier: NCT00478205.

Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease.

OBJECTIVE: To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI)-measured behavioural symptoms. METHODS: Two randomised, double-blind, parallel-group, placebo-controlled studies that met prespecified criteria and were sufficiently similar to allow data pooling were derived from all donepezil AD clinical trials. Patients scoring from 10 to 26 on baseline Mini-Mental Status Examination were included. A clinical milestone for apathy and other NPI items was defined as the first emergence of a composite score (frequency × severity) ≥ 3. Differences in time to event (i.e. milestone) between donepezil- and placebo-treated groups were assessed using the Kaplan-Meier method and log-rank test. Shift tables were constructed to evaluate clinical milestone status for apathy and other NPI items at baseline and endpoint, and were analysed using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline status. RESULTS: Of all NPI items, apathy had the highest proportion of subjects scoring ≥ 3 at baseline. Donepezil was superior to placebo on both apathy milestone analyses (time-to-event log-rank test and shift table CMH test, p = 0.01). Aberrant motor behaviour demonstrated similar benefit. CONCLUSIONS: Donepezil treatment appears to have resulted in a significant reduction over 6 months of the emergence of apathy in patients with AD. These data suggest that a prospective clinical trial in patients with early AD that includes apathy as a primary outcome measure may be warranted.

Effect of donepezil on cognition in severe Alzheimer's disease: a pooled data analysis.

To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total scores from baseline to week 24 was 6.22 (p < 0.0001, Cohen's d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6-9 stratum (LS mean difference, 7.60; p < 0.0001, Cohen's d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohen's d, 0.17-0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.

Efficacy and safety of donepezil in patients with Alzheimer's disease in assisted living facilities.

The aim of this 12-week, open-label study was to determine the safety and efficacy of donepezil in participants with Alzheimer's disease (AD) residing in assisted living facilities (ALFs). Participants received 5 mg donepezil daily for 6 weeks followed by 10 mg daily for 6 weeks. Primary and secondary outcomes were change from baseline in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory 8 (NPI-8) scores, respectively. Safety was assessed by adverse events (AEs) and laboratory tests. Of the 97 participants, 76 completed the study. Mean MMSE score (18.7 at baseline) improved 1.8 points (P < .0001) at study end. Total NPI-8 score improved 1.8 points (P = .043). The most frequent AEs were nausea and diarrhea. Donepezil improved cognition and behavior and was safe and well tolerated. The results suggest a need for proactive screening and diagnosis of AD and support the value of treatment and use of donepezil in participants residing in ALFs.

Effectiveness and safety of donepezil in Hispanic patients with Alzheimer's disease: a 12-week open-label study.

BACKGROUND: Hispanics represent 10% of the U.S. population and are the fastest growing group. Studies show a higher prevalence and incidence of Alzheimer's disease (AD) in Hispanics than in the non-Hispanic white population, with an earlier age of onset. Among the currently estimated 200,000 Hispanics with AD, a significant number remain undiagnosed and untreated, and Hispanic participation in AD clinical trials has been historically low. This study evaluated the efficacy and safety of donepezil hydrochloride (donepezil) in Hispanics with mild-to-moderate AD. METHODS: In this multicenter, open-label, 12-week study conducted in the United States, subjects were Hispanic men or women aged > or =50 years with a diagnosis of mild-to-moderate AD (DSMV-IV and NINCDS/ADRDA criteria), with Mini-Mental State Examination (MMSE) scores of 10-26 (inclusive) at screening. Subjects were treated with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for 6 weeks. Clinical evaluation was performed at baseline, week 6 and week 12. Cognitive improvement was measured using the MMSE, Fuld Object Memory Evaluation (FOME) and Symbol Digit Modality Test (SDMT). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI). RESULTS: One-hundred-six patients with mild-to-moderate AD (mean age 68.6 years) were enrolled (intent to treat, n=97); most chose to have assessments conducted in Spanish. With 12 weeks of treatment, subjects showed statistically significant improvement from baseline on MMSE (P<0.0001), FOME retrieval (P=0.0042), FOME repeated retrieval (P=0.0020) and SDMT correct scores (P<0.0001). The NPI subdomain "apathy/indifference" showed statistically significant improvement (P=0.0010).The NPI Caregiver Distress scale (NPI-D) total score was statistically significantly improved (P=0.0500), suggesting a positive impact on relieving caregivers' burden associated with patient behavior. Most patients tolerated the treatment well, with only 2 discontinuing because of adverse events. The most common (>5%) adverse events were insomnia (9.5%), dizziness (7.6%), diarrhea (5.7%) and nausea (5.7%). CONCLUSION: The cognitive improvement and safety results from this study were consistent with those reported for donepezil in the general population. Increased awareness of AD in the Hispanic population will help more Hispanics with AD to benefit from early diagnosis and effective treatment.

Behavioral effects of current Alzheimer's disease treatments: a descriptive review.

BACKGROUND: Behavioral abnormalities and neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). Many clinical trials of cholinesterase inhibitors (ChE-Is) and memantine have included behavioral measures as primary or secondary outcomes, and most have observed behavioral benefits in conjunction with treatment. The purpose of this review was to determine the frequency of positive behavioral outcomes in AD clinical trials and clinical reports, to determine the symptoms most responsive to antidementia agents, and to explore factors that correlate with negative outcomes in clinical trials of antidementia agents with regard to behavioral measures. METHODS: We performed a computerized search of randomized clinical trials and open-label studies of ChE-Is and memantine for AD including a behavioral outcome measure. Studies involving 10 or more patients using therapeutic doses of the target agents and including a behavioral measure as a primary or secondary outcome were included in this review. RESULTS: One hundred fifty-seven peer-reviewed articles and 68 publicly presented abstracts were identified in the literature search. Subsequent review established that 15 publications arising from 13 randomized, double-blind, placebo-controlled AD trials met the review inclusion criteria. Positive outcomes on behavioral measures were reported in 8 of 15 publications as a primary or secondary outcome. In most blinded AD clinical trials, behavioral measures were secondary outcomes. Mood symptoms and apathy have most commonly responded to ChE-Is, whereas memantine has been associated with a reduction in irritability and agitation. However, there is substantial variability among trials in terms of behavioral outcomes. Studies that assessed patients with more severe dementia, included patients with less severe behavioral disturbances at baseline, involved institutionalized patients, or were international in scope tended to have negative outcomes. In institutionalized patients there is commonly an improvement in the placebo group that confounds the observation of any drug-placebo difference. CONCLUSIONS: Antidementia agents have been associated with beneficial behavioral outcomes in many randomized clinical trials and open-label studies. Most studies are not designed to test the psychotropic properties of antidementia drugs. Trials with negative behavioral outcomes are most likely to involve patients who are institutionalized and have few behavioral disturbances at baseline. Clinical trials designed to assess behavioral effects of antidementia agents should anticipate these factors.

Reduced mortality rates after intensive statin therapy in managed-care patients.

OBJECTIVE: To evaluate whether intensive statin therapy in a managed-care setting produces greater clinical benefit than more moderate statin use. METHODS: Adults hospitalized for a coronary heart disease (CHD) event were identified from a longitudinal database of pharmaceutical and medical claims. Propensity scores representing a patient's likelihood of receiving statin therapy were calculated. Statin-treated patients were those who received statin therapy within 30 days of hospital discharge after a CHD event, had been supplied with statin therapy for at least 10 days during the follow-up period, and received statin therapy for at least 10 days before the first recurrent CHD event. Standard or intensive statin therapy was identified according to low-density lipoprotein cholesterol reductions expected with statin dose. Patients in the standard and intensive groups were matched by propensity scores to patients not receiving statin therapy after discharge. Patients in the standard statin therapy group were also matched to patients who received intensive statin therapy. Mortality rates after hospital discharge were compared in all matched groups. RESULTS: Patients treated with standard therapy experienced a 32% reduction in risk of death compared with patients not receiving statin therapy (P = 0.003). Patients who received intensive statin therapy after a CHD event experienced a 42% reduction in risk of mortality (P = 0.002) versus those not receiving statin therapy. Compared with standard therapy, intensive statin treatment further reduced the risk of death by 29% (P = 0.020). CONCLUSIONS: High risk CHD patients benefit from intensive statin therapy in a real-world, managed-care cohort, confirming the results of randomized clinical trials.

Relationship between preventative physical health care and mental health in individuals with schizophrenia: a survey of caregivers.

The relationship between preventative physical health care and mental health in individuals with schizophrenia was assessed retrospectively by questionnaires completed by 504 caregivers. Psychiatric symptom severity and quality-of-life data on 332 respondents were evaluable. Suboptimal preventative physical health care was defined as absence of > or =2 examinations within a specified time: physical and dental within 12 months, eye within 24 months. Findings revealed similar use of mental health care services for all individuals, but those in the suboptimal physical health care group (n = 93 [28%]) had a lower quality of life (p < .011), more negative symptoms (p < .009), less paid employment (p < .001), and more alcohol/drug abuse (p = .02). These findings suggest that mental health care providers should play a more active role in monitoring the basic physical health care of patients with schizophrenia.

Economic consequences of the adverse reactions related with antipsychotics: an economic model comparing tolerability of ziprasidone, olanzapine, risperidone, and haloperidol in Spain.

Frequency of adverse reactions (ARs) related with antipsychotics usage is high. Along with clinical implications, economic impact might be important. The purpose of this study was to model the economic consequences of ARs related with ziprasidone, olanzapine, risperidone, and haloperidol in Spain, by means of a cost-effectiveness model developed using a Markov modeling approach. The model simulated treatment of a cohort of 1000 schizophrenics for 12 months, initiating treatment with one of four antipsychotic drugs; haloperidol, risperidone, olanzapine and ziprasidone. Conditional probabilities of developing any of four adverse events were calculated. Treatment was modified (decrease dose, switch medication) according to incidence of ARs and physician judgments, obtained from a local cross-sectional study and clinical trials previously published. The analysis was conducted in year 2002 from a third party payer perspective. Results are shown as annual cost per month with psychotic symptoms controlled and included univariate sensitivity analysis. The therapeutic strategy starting with ziprasidone showed the lower costs and the greater number of months with symptoms controlled in most scenarios evaluated versus the other options considered, although the differences were weak: 9.6, 9.3, 9.5 and 9.5 controlled months per patient in base scenario, with annual cost per patient per month with symptoms controlled of 1035 Euros, 1084 Euros, 1087 Euros and 1090 Euros for ziprasidone, haloperidol, risperidone and olanzapine, respectively. Results were robust to one-way sensitivity analysis. Despite the unlike drug prices of antipsychotics, a considerable economic impact due to adverse reactions was seen in our setting. These results should be taken into account by health decision makers and clinicians in the management of patients with schizophrenia.

Reliability of monitoring the clinical dementia rating in multicenter clinical trials.

CONTEXT: The Clinical Dementia Rating (CDR) is quickly becoming a criterion standard in multicenter clinical trials in Alzheimer disease. An abbreviated version, with formal monitoring for consistency across sites and raters, is currently used in the Alzheimer's Disease Cooperative Study (ADCS). OBJECTIVE: To demonstrate the degree of agreement on CDR scoring of clinical monitors working independently from ADCS-CDR worksheets. DESIGN: Three members of the ADCS who are experienced and highly trained with respect to the CDR independently reviewed the ADCS-CDR worksheets of 15 subjects, assigning box and global CDR scores according to the prescribed algorithm. SETTING: The ratings were assigned during a single, 3-hour session in a closed room. PARTICIPANTS: Two clinical monitors and one project director/clinical monitor supervisor. MAIN OUTCOME MEASURES: Percent agreement, Kendall's tau-b, and Cohen's kappa were used to assess the degree of agreement of the raters with the previously established gold standard assessment on global and box scores for the 15 subjects. RESULTS: Raters, blinded to patient groupings, were in agreement with the Gold Standard global CDR assessment on 87% of ratings. Kappa values indicated good (kappa = 0.66, orientation and judgment & problem solving boxes) to excellent (kappa = 0.83, global CDR) agreement. CONCLUSIONS: The ADCS-CDR worksheets were reliably and consistently scored by clinical monitors, who may be considered proxy gold standards for CDR assessment.