Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.

BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).

Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis.

OBJECTIVE: To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy. METHODS: The presence or absence of both immunoglobulin (Ig) G and IgM oligoclonal bands (OCB) was blindly examined in paired cerebrospinal fluid (CSF) and serum samples from a large PPMS patient cohort, and related to clinical and imaging evidence of focal inflammatory disease activity. RESULTS: Using both cross-sectional samples and serial sampling in a subgroup of patients followed prospectively as part of the placebo-controlled OLYMPUS study of rituximab in PPMS, we found that the presence of CSF-restricted IgM OCB (but not of IgG OCB) is associated with an active inflammatory disease phenotype in PPMS patients. This finding was confirmed in an independent, multicenter validation cohort. INTERPRETATION: The presence of CSF IgM OCB may be a biomarker for a subset of PPMS patients with more active inflammatory disease, who may benefit from immune-directed treatments.

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study.

INTRODUCTION: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD. METHODS: We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex(®) with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aß1-40 and Aß1-42 in plasma and levels of Aß1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. RESULTS: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex(®) was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). CONCLUSIONS: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex(®) in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00099710.

Revision of the criteria for Alzheimer's disease: A symposium.

The current criteria for classification of Alzheimer's disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimer's Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance-based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD.

Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF in rhesus monkeys.

Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson's disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6-9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 microg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 microl/day flow rate) for 6 months; a subset of animals (2-3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 microg/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 microg/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-microg/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.

Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) in rhesus monkeys.

Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson's disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6-9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 micro g/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 micro l/day flow rate) for 6 months; a subset of animals (2-3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 micro g/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 micro g/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-micro g/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.

Development of a maturing T-cell-mediated immune response in patients with idiopathic Parkinson's disease receiving r-metHuGDNF via continuous intraputaminal infusion.

The development of a maturing T-cell-mediated immune response was characterized in Parkinson's disease subjects receiving recombinant human glial-derived neurotrophic factor (r-metHuGDNF) via continuous bilateral intraputaminal infusion. Eighteen of 34 subjects tested positive for anti-r-metHuGDNF-binding antibodies. Four subjects developed neutralizing activity, three of which demonstrated classic immunoglobulin class switching from IgM to IgG. An increase of anti-r-metHuGDNF IgG-binding antibodies correlated with the development of neutralizing activity. All serum samples from two subjects with neutralizing activity were characterized for IgG subclasses. These data revealed an initial anti-r-metHuGDNF IgG population where IgG1 >> IgG2 >> IgG4, and IgG3 concentrations were negligible. However, continued antigenic stimulation resulted in concentration changes where IgG4 > IgG1> IgG2, indicating a mature immune response. In addition, using in silico techniques, two immunodominant MHC class II T-cell epitopes were predicted for the native GDNF sequence. These data demonstrate development of a mature T-cell-mediated immune response in these subjects.

Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men.

CONTEXT: There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD). OBJECTIVE: To evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with mild AD and healthy elderly men. DESIGN: Twenty-four-week, randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Memory disorders clinics as well as general neurology and medicine clinics from University of California medical centers at Los Angeles, San Francisco, and Irvine. PATIENTS OR OTHER PARTICIPANTS: Sixteen male patients with AD and 22 healthy male control subjects. Healthy elderly control men were recruited from the community through advertisements as well as through the university-based clinics. INTERVENTION: Testosterone and placebo, in the form of hydroalcoholic gel (75 mg), were applied daily to the skin of the participants. MAIN OUTCOME MEASURES: Instruments assessing cognitive functioning (Alzheimer's Disease Assessment Scale-Cognitive Subscale, California Verbal Learning Test, Block Design Subtest, Judgment of Line Orientation, Developmental Test of Visual-Motor Integration), neuropsychiatric symptoms (Neuropsychiatric Inventory), global functioning (Clinician's Interview-Based Impression of Change), and quality of life (Quality of Life-Alzheimer Disease Scale). RESULTS: For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale (P = .01). No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo. In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group (P = .09) compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures. Testosterone treatment was well tolerated with few adverse effects relative to placebo. CONCLUSIONS: Results suggest that testosterone replacement therapy improved overall quality of life in patients with AD. Testosterone had minimal effects on cognition.

Clinical characteristics in early Parkinson's disease in a central California population-based study.

There is considerable variation in the phenotypic appearance of individuals with idiopathic Parkinson's disease (PD), which may translate into differences in disease progression in addition to underlying disease etiology. In this publication, we report on the demographic and clinical characteristics of 162 individuals diagnosed with clinically probable PD from January 1998 to June 2003 who resided in predominantly rural communities in central California. The majority of the subjects were Caucasian, male, and between 60 and 79 years of age. The akinetic-rigid and tremor-dominant subtypes were more common than the mixed subtype. The majority of subjects displayed motor signs of rigidity (92.0%), bradykinesia (95.7%), and gait problems (87.0%), whereas less than half (43.3%) of the subjects displayed a tremor. Three fourths of patients received a Hoehn and Yahr Scale score of Stage 2 or higher. One third of the patients were treated with levodopa, and patients under 60 years of age were more likely to be treated with dopamine agonists. Within 3 years after first diagnosis, 13% of subjects showed some signs of depression and 17% of subjects met criteria for mild dementia. Among our subjects, 17.3% reported a family history of PD in first- or second-degree relatives,15.4% a family history of essential tremor, and 14.2% of Alzheimer's disease. This study represents the most extensive phenotypic description of rural U.S. residents in the initial stages of PD who were recruited in a population-based manner; future follow-up may provide valuable information regarding the prognostic indication of these symptoms/signs and improve our understanding of the underlying etiology of PD.

A potential role of the curry spice curcumin in Alzheimer's disease.

There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimer's disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology.

Neuropsychiatric symptoms and quality of life in Alzheimer disease.

OBJECTIVE: Authors examined the impact of neuropsychiatric symptoms in Alzheimer disease (AD) patients' and caregivers' quality of life (QOL) and assessed the relationship of caregiver distress to neuropsychiatric symptoms and caregiver QOL. METHODS: Sixty-two patients with probable or possible AD and their caregivers participated. Neuropsychiatric symptoms of patients were assessed with the Neuropsychiatric Inventory (NPI). QOL of both patients and caregivers was assessed using the QOL-Alzheimer's Disease (QOL-AD) scale. Each patient and caregiver completed patient QOL ratings; caregivers also completed caregiver QOL assessments. RESULTS: Caregiver QOL-AD was negatively correlated with agitation/aggression, anxiety, disinhibition, irritability/lability, and total NPI score. Patient QOL on both patient and caregiver ratings was negatively correlated with depression. Patient-reported QOL-AD ratings at different levels of cognitive functioning were not correlated with caregiver-reported ratings. The lack of relationship between patient and caregiver assessments of patient QOL was evident in both mildly and moderately affected patients. Caregiver QOL was negatively correlated with distress related to agitation/aggression, disinhibition, irritability/lability, and total NPI distress. CONCLUSION: Neuropsychiatric symptoms of AD patients adversely affect both patient and caregiver QOL. These results suggest that identifying and treating neuropsychiatric symptoms in AD may improve both patient and caregiver QOL.

Role of Cholinesterase Inhibitors in Managing Behavioral Problems in Alzheimer's Disease.

Alzheimer's disease is characterized by progressive cognitive and functional decline and the emergence of behavioral disturbances. Behavioral symptoms, in particular, cause great distress to caregivers, creating an emotional and financial burden that often prompts the caregiver to place the patient in a nursing facility. The clinical deterioration in Alzheimer's disease is, in part, a result of deficits involving several neurochemical pathways. The cholinergic system, which is the most consistently and dramatically affected neurotransmitter system in Alzheimer's disease, has been strongly implicated in the emergence of neuropsychiatric symptoms. This article reviews evidence suggesting that, in addition to effects on cognition and function, the cholinesterase inhibitors benefit the behavioral symptoms of Alzheimer's disease. Pharmacologic and nonpharmacologic treatment strategies for the management of behavioral symptoms are discussed.

Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease.

BACKGROUND: Serotonin has been linked to neuropsychiatric symptoms in Alzheimer disease, mainly agitation/aggression, depression, and psychosis. Neuropsychiatric symptoms have been associated with polymorphisms of the promoter region (5-HTTPR ) and intron 2 of the serotonin transporter gene (5-HTTVNTR) or the 5-HT2A and 5-HT2C receptor genes in some but not all studies. OBJECTIVE: To examine the association of the serotonin promoter, transporter, and receptor genes with neuropsychiatric symptoms in patients with Alzheimer disease. METHODS: The sample included 96 patients with Alzheimer disease from the outpatient clinic of the University of California Los Angeles Alzheimer's Disease Research Center, Los Angeles. The Neuropsychiatric Inventory was used to measure neuropsychiatric symptoms, and blood samples were available for genetic analysis. Based on the literature, we hypothesized that the 5-HT2A and 5-HT2C receptor polymorphisms would be associated with agitation/aggression and psychosis and the 5-HTTPR or 5-HTTVNTR polymorphisms, with agitation/aggression or depression and anxiety. One-way analyses of variance were performed with age, ethnicity, sex, or education as covariates. RESULTS: The 102T genotype of the 5-HT2A receptor was significantly associated with delusions (P =.045) and agitation/aggression (P =.002). We did not replicate previous associations of the 5-HT2C receptor polymorphism with psychosis or of the 5-HTTPR polymorphism with agitation/aggression, psychosis, or depression. We did not find any associations with the 5-HTTVNTR polymorphism and agitation/aggression, depression, or anxiety. CONCLUSIONS: The 5-HT2A receptor polymorphism may contribute to the expression of psychosis and agitation/aggression in patients with Alzheimer disease. Absence of other positive associations may be due to the relatively small sample size and/or potentially small effect size of the polymorphisms and requires further study.

Mild cognitive impairment is associated with characteristic neuropsychiatric symptoms.

Mild cognitive impairment (MCI) has emerged as an identifiable condition and in many cases is a transitional state preceding diagnosable Alzheimer disease (AD). Neurobiological and neuroimaging characteristics of amnestic-type MCI have been investigated, but few comprehensive neuropsychiatric studies have been reported. The aim of this preliminary study was to define the neuropsychiatric features of the amnestic-type MCI and compare them with those of mild AD and normal controls. The Neuropsychiatric Inventory (NPI) was used to assess the neuropsychiatric symptoms in three age and education comparable groups, i.e., 28 MCI, 124 mild AD, and 50 normal subjects. Individual subscores of the 10 NPI symptoms and total NPI scores were compared between the MCI patients and the other 2 groups. The results of this preliminary investigation showed that MCI patients frequently manifested neuropsychiatric symptoms. The most common symptoms in the MCI group were dysphoria (39%), apathy (39%), irritability (29%), and anxiety (25%). There were significant differences in apathy, dysphoria, irritability, anxiety, agitation, and aberrant motor behavior between the MCI and control groups; in contrast, only delusions were significantly less common in MCI compared with mild AD. There was a significant difference between the MCI and control groups on total NPI scores (p = 0.001), but not between the MCI and mild AD groups (p = 0.304). Amnestic MCI is associated with significant neuropsychiatric symptoms, especially mood disturbances and apathy. Psychotic symptoms are significantly more common in the early stage of AD than in MCI. These results are derived from a limited clinical sample and require confirmation in longitudinal community-based investigations.

Relational integration and executive function in Alzheimer's disease.

Executive functions depend on the ability to represent relations between objects and events, and the prefrontal cortex provides the neural substrate for this capacity. Patients with probable Alzheimer's disease (AD) and control participants were administered measures of working memory and reasoning that varied systematically in their relational complexity. AD patients showed impairment on reasoning measures that required the online integration of relations but performed as well as control participants on nonrelational items and items requiring the processing of only single relations. When AD patients were divided into subgroups based on their performance on relational reasoning measures, the subgroup that showed significant impairment on relational integration measures exhibited a neuropsychological profile consistent with prefrontal cortical dysfunction.

Curricular framework: core competencies in multicultural geriatric care.

Strategies to reduce the documented disparities in health and health care for the rapidly growing numbers of older patients from diverse ethnic populations include increased cultural competence of providers. To assist geriatric faculty in medical and other health professional schools develop cultural competence training for their ethnogeriatric programs, the University of California Academic Geriatric Resource Program partnered with the Ethnogeriatric Committee of the American Geriatrics Society to develop a curricular framework. The framework includes core competencies based on the format of the Core Competencies for the Care of Older Patients developed by the Education Committee of the American Geriatrics Society. Competencies in attitudes, knowledge, and skills for medical providers caring for elders from diverse populations are specified. Also included are recommended teaching strategies and resources for faculty to pursue the development of full curricula.

Regression to the mean: implications for clinical trials of psychotropic agents in dementia.

Effective drug development depends on understanding and optimizing results from controlled clinical trials. A recent double-blind, randomized, controlled trial of the treatment of agitation in patients with Alzheimer's disease (AD) found no difference among the four arms of the study: haloperidol, trazodone, behavioral therapy, placebo. The current analysis was undertaken to further investigate the issues bearing on this outcome and to identify better means of detecting psychotropic effects in trials involving patients with AD. This was post hoc analysis of a clinical trial data set. Patients in the placebo group were divided into responders (25% reduction in symptoms), worseners (25% worsening in baseline agitation scores), and those without a change in symptoms. Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean. Patients exhibiting greater improvement had more severe baseline behavioral disturbances. The relatively modest severity of agitation and the low medication doses achieved in the study may have further contributed to the failure to distinguish among treatment groups. Research design adjustments such as collection of both screening and baseline measures to determine eligibility may limit the effects of regression to the mean on trial outcomes and reduce this challenge to clinical trials.