Clinician Interview-Based Impression Of Change Research Articles

Pharmaceutical interventions for emotionalism after stroke.

Antidepressants may be useful in the treatment of abnormal crying associated with stroke. This is an update of a Cochrane Review first published in 2004 and last updated in 2019. To evaluate the benefits and harms of pharmaceutical treatment in people with emotionalism after stroke. We searched the Cochrane Stroke Group Register, CENTRAL, MEDLINE, Embase, four other databases, and three trials registers (May 2022). We included randomised controlled trials (RCTs) and quasi-RCTs comparing psychotropic medication to placebo in people with stroke and emotionalism (also known as emotional lability, pathological crying or laughing, emotional incontinence, involuntary emotional expression disorder, and pseudobulbar affect). Two review authors independently selected trials, assessed risk of bias, extracted data from all included trials, and used GRADE to assess the certainty of the body of evidence. We calculated the mean difference (MD) or standardised mean difference (SMD) for continuous data and the risk ratio (RR) for dichotomous data, with 95% confidence intervals (CIs). We assessed heterogeneity using the I² statistic. The primary emotionalism measures were the proportion of participants achieving at least a 50% reduction in abnormal emotional behaviour at the end of treatment, improved score on the Center for Neurologic Study - Lability Scale (CNS-LS) or Clinician Interview-Based Impression of Change (CIBIC), or diminished tearfulness. We did not identify any new trials for this update. We included seven trials with a total of 239 participants. Two trials had a cross-over design, but outcome data were not available from the first phase (precross-over) in an appropriate format for inclusion as a parallel randomised controlled trial (RCT). Thus, the results of the review are based on five trials with a total of 213 participants. It is uncertain whether fluoxetine increases the number of people who have a 50% reduction in emotionalism when compared to placebo (risk ratio (RR) 0.26, 95% CI 0.09 to 0.77; P = 0.02; 1 trial, 19 participants) because the certainty of evidence is very low. Sertraline may lead to little to no difference in Center for Neurologic Study - Lability Scale (CNS-LS) scores and Clinician Interview-Based Impression of Change (CIBIC) scores when compared to placebo (RR 0.20, 95% CI 0.03 to 1.50; P = 0.12; 1 trial, 28 participants; low-certainty evidence). Antidepressants probably increase the number of people who experience a reduction in tearfulness (RR 0.32, 95% CI 0.12 to 0.86; P = 0.02; 3 trials, 164 participants; moderate-certainty evidence). No trials were found that evaluated the impact of other pharmaceutical interventions. Only two trial authors systematically recorded and reported adverse events, resulting in limited data on the potential harms of treatment. Six trials reported death as an adverse event and found no difference between the groups (antidepressants versus placebo) in the number of deaths reported (RR 0.59, 95% CI 0.08 to 4.50; P = 0.61; 172 participants; moderate-certainty evidence). This review provides very low- to moderate-certainty evidence that antidepressants may reduce the frequency and severity of emotionalism. The included trials were small and had some degree of bias. Antidepressants may reduce the frequency and severity of crying or laughing episodes when compared to placebo, based on very low-certainty evidence. Our conclusions must be qualified by several methodological deficiencies in the trials and interpreted with caution despite the effect being very large. The effect does not seem specific to one drug or class of drugs. More reliable data are required before appropriate conclusions can be made about the treatment of post-stroke emotionalism. Future trialists investigating the effect of antidepressants in people with emotionalism after stroke should consider developing and using a standardised method to diagnose emotionalism, determine severity, and assess change over time; provide treatment for a sufficient duration and follow-up to better assess rates of relapse or maintenance; and include careful assessment and complete reporting of adverse events.

Comparative effect of propofol and sevoflurane on chronic postsurgical pain and cognitive function after cardiac surgery in Chinese elderly patients: A preliminary clinical study


 
 
 
 Purpose: To compare the effects of propofol and sevoflurane on chronic post-surgical pain and cognitive function after cardiac surgery in Chinese elderly patients.
 Methods: A total of 200 Chinese patients (aged > 65 years) with confirmed diagnosis of severe chronic artery disease who underwent cardiac surgery were given either propofol or sevoflurane. The following efficacy variables were assessed in both treatment groups: pain using an 11-point NRS after surgery; cognitive function, using Severe Impairment Battery (SIB), Clinician Interview-Based Impression of Change (CIBIC), Mini Mental State Examination (MMSE) scale; as well as psychological well-being and disability, using K10 Psychological Distress Scale K-10 and WHO Disability Assessment Schedule (WHODAS) scale. Incidence of complications and duration of hospital stay were also compared.
 Results: Pain severity score was significantly lower in patients treated with propofol than in those who received sevoflurane (6.1 vs 8.4; p < 0.05). Psychological well-being measured using K-10 score was similar in both groups (p >0.05). Similarly, there were no meaningful differences in disability score between the two treatment groups (p > 0.05). The severity of signs and symptoms of dementia were similar at baseline visit (p >0.05). Propofol-treated patients had numerically greater relief in signs and symptoms of dementia/cognitive impairment, when compared to the Sevoflurane-treated patients (p >0.05). However, incidence of complications (including adverse events) was comparable in both groups (p > 0.05).
 Conclusion: Propofol produced significantly greater improvement in post-surgical pain and cognitive functions than sevoflurane after cardiac surgery in Chinese elderly patients.
 
 
 

A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimer's Disease.

Background and PurposeOral administration of cholinesterase inhibitors is often associated with adverse gastrointestinal effects, and so developing an alternative administration route, such as transdermal, is urgently needed. The primary objective of this study was to determine the efficacy and safety of the IPI-301 donepezil transdermal patch compared with donepezil tablets (control) in mild-to-moderate probable Alzheimer’s disease (AD).MethodsThis prospective, randomized, double-blind, double-dummy, two-arm parallel, multicenter trial included 399 patients, among whom 303 completed the trial. For randomization, the patients were stratified based on previous treatment and donepezil dose; patients in each stratum were randomized to the test and control groups at a 1:1 ratio.ResultsThe difference between the control group and the IPI-301 group, quantified as the Hodges–Lehmann estimate of location shift, was 0.00 (95% confidence interval: -1.00 to 1.33), with an upper limit of less than 2.02. The change in Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score differed significantly between the IPI-301 and control groups (p=0.02). However, the changes in the full-itemized ADCS-ADL scores at week 24 did not differ significantly between the two groups. There were no differences between the two groups regarding the scores for the Clinician Interview-Based Impression of Change (p=0.9097), Mini-Mental State Examination (p=0.7018), Neuropsychiatric Inventory (p=0.7656), or Clinical Dementia Rating (p=0.9990). Adverse events, vital signs, and laboratory test results were comparable between the two groups.ConclusionsIPI-301 was safe and efficacious in improving cognitive function in patients with mild-to-moderate AD.

Pharmaceutical interventions for emotionalism after stroke.

Antidepressants may be useful in the treatment of abnormal crying associated with stroke. This is an update of a Cochrane Review first published in 2004 and last updated in 2010. To determine whether pharmaceutical treatment reduces the frequency of emotional displays in people with emotionalism after stroke. We searched the trial register of Cochrane Stroke (last searched May 2018). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; to May 2018), MEDLINE (1966 to 14 May 2018), Embase (1980 to 14 May 2018), CINAHL (1982 to 14 May 2018), PsycINFO (1967 to 14 May 2018), BIOSIS Previews (2002 to 14 May 2018), Web of Science (2002 to 14 May 2018), WHO ICTRP (to 14 May 2018), ClinicalTrials.gov (to 14 May 2018), and ProQuest Dissertations and Theses Database (to 14 May 2018). Randomised controlled trials (RCTs) and quasi-RCTs comparing psychotropic medication to placebo in people with stroke and emotionalism (also known as emotional lability, pathological crying or laughing, emotional incontinence, involuntary emotional expression disorder, and pseudobulbar affect). Two review authors independently selected studies, assessed risk of bias, extracted data from all included studies, and used GRADE to assess the quality of the body of evidence. We calculated mean difference (MD) or standardised mean difference (SMD) for continuous data and risk ratio (RR) for dichotomous data with 95% confidence intervals (CIs). We assessed heterogeneity using the I2 statistic. The primary emotionalism measures were the proportion of participants achieving at least a 50% reduction in abnormal emotional behaviour at the end of treatment, improved score on Center for Neurologic Study - Lability Scale (CNS-LS), Clinician Interview-Based Impression of Change (CIBIC) or diminished tearfulness. We included seven trials with a total of 239 participants. Two trials were of cross-over design, and outcome data were not available from the first phase (precross-over) in an appropriate format for inclusion as a parallel randomised controlled trial (RCT). Thus, the results of the review are based on five trials with 213 participants. Treatment effects were observed on the following primary endpoints of emotionalism: There is very low quality of evidence from one small RCT that antidepressants increased the number of people who had 50% reduction in emotionalism (RR 16.50, 95% CI 1.07 to 253.40; 19 participants) and low quality evidence from one RCT of improved scores on Center for Neurologic Study - Lability Scale (CNS-LS) and Clinician Interview-Based Impression of Change (CIBIC) with antidepressants (RR 1.44, 95% CI 0.95 to 2.19; 28 participants). There was moderate quality evidence from three RCTS that they increased the number of people who had a reduction in tearfulness (RR 2.18, 95% CI 1.29 to 3.71; 164 participants); and low quality evidence from one RCT of improved scores on the Pathological Laughter and Crying Scale (PLCS) (MD 8.40, 95% CI 11.56 to 5.24; 28 participants).Six trials reported adverse events (death) and found no difference between the groups in death (RR 0.59, 95% CI 0.08 to 4.50; 6 RCTs, 172 participants, moderate-quality evidence). Antidepressants may reduce the frequency and severity of crying or laughing episodes based on very low quality evidence. Our conclusions must be qualified by several methodological deficiencies in the studies and interpreted with caution despite the effect being very large. The effect does not seem specific to one drug or class of drugs. More reliable data are required before appropriate conclusions can be made about the treatment of post-stroke emotionalism. Future trialists investigating the effect of antidepressants in people with emotionalism after stroke should consider developing and using a standardised method to diagnose emotionalism, determine severity and assess change over time; provide treatment for a sufficient duration and follow-up to better assess rates of relapse or maintenance and include careful assessment and complete reporting of adverse events.

The efficacy and safety of Fufangdanshen tablets (Radix Salviae miltiorrhizae formula tablets) for mild to moderate vascular dementia: a study protocol for a randomized controlled trial.

BackgroundVascular dementia (VaD) is the second most common subtype of dementia after Alzheimer's disease (AD). Currently, there are no medications approved for treating patients with VaD. Fufangdanshen (FFDS) tablets (Radix Salviae miltiorrhizae formula tablets) are a traditional Chinese medicine that has been reported to improve memory. However, the existing evidence for FFDS tablets in clinical practice derives from methodologically flawed studies. To further investigate the safety, tolerability, and efficacy of FFDS tables in the treatment of mild to moderate VaD, we designed and reported the methodology for a 24-week randomized, double-blind, parallel, multicenter study.Methods/designThis ongoing study is a double-blind, randomized, parallel placebo-controlled trial. A total of 240 patients with mild to moderate VaD will be enrolled. After a 2-week run-in period, the eligible patients will be randomized to receive either three FFDS or placebo tablets three times per day for 24 weeks, with a follow-up 12 weeks after the last treatment. The primary efficacy measurement will be the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinician Interview-Based Impression of Change (CIBIC-plus). The secondary efficacy measurements will include the Mini Mental State Examination (MMSE) and activities of daily living (ADL). Adverse events will also be reported.DiscussionThis randomized trial will be the first rigorous study on the efficacy and safety of FFDS tablets for treating cognitive symptoms in patients with VaD using a rational design.Trial registrationClinicalTrials.gov: NCT01761227. Registered on 2 January 2013.

Response to cholinesterase inhibitors affects lifespan in Alzheimer's disease.

BackgroundA varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer’s disease (AD). Whether the individual-specific response, specific ChEI agent or dose affects mortality is unclear. We aimed to examine the relationship between the 6-month response to ChEI and lifespan.MethodsSix hundred and eighty-one deceased patients with a clinical AD diagnosis and a Mini-Mental State Examination (MMSE) score of 10–26 at the start of ChEI therapy (baseline) were included in a prospective, observational, multicentre study in clinical practice. At baseline and after 6 months of treatment, the participants were assessed using the MMSE, the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician’s Interview-Based Impression of Change (CIBIC), the Instrumental Activities of Daily Living (IADL) scale, and the Physical Self-Maintenance Scale (PSMS). The individuals’ socio-demographic characteristics, ChEI dose, and date of death were recorded. Responses to ChEI and the association of possible risk factors with survival were analysed using general linear models.ResultsA longer lifespan (mean of 0.5 years) was observed among the improved/unchanged patients, as measured by MMSE or CIBIC score, but not by ADAS-cog score, after 6 months of ChEI therapy. In the multivariate models, increased survival time was independently related to a better 6-month response in MMSE, CIBIC, IADL, and PSMS scores, female sex, no antihypertensive/cardiac or antidiabetic therapy, younger age, lower education, milder disease stage at baseline, and higher ChEI dose. Apolipoprotein E genotype did not affect mortality significantly. The patients who received a higher ChEI dose during the first 6 months had a mean lifespan after baseline that was 15 months longer than that of those who received a lower dose.ConclusionsA better short-term response to ChEI might prolong survival in naturalistic AD patients. In individuals who received and tolerated higher ChEI doses, a longer lifespan can be expected.

A Randomized, Double-blind, Placebo-Controlled Study of Latrepirdine in Patients With Mild to Moderate Huntington Disease

BACKGROUND Latrepirdine is an orally administered experimental small molecule that was initially developed as an antihistamine and subsequently was shown to stabilize mitochondrial membranes and function, which might be impaired in Huntington disease. OBJECTIVE To determine the effect of latrepirdine on cognition and global function in patients with mild to moderate Huntington disease. DESIGN Randomized, double-blind, placebo-controlled study. SETTING Sixty-four research centers in Australia, Europe, and North America. PATIENTS Four hundred three patients with mild to moderate Huntington disease and baseline cognitive impairment (Mini-Mental State Examination score, 10-26). INTERVENTION Latrepirdine (20 mg) vs matching placebo administered orally 3 times daily for 26 weeks. MAIN OUTCOME MEASURES The co-primary outcome measures were cognition as measured by the change in Mini-Mental State Examination score from baseline to week 26 and global function at week 26 as measured by the Clinician Interview-Based Impression of Change, plus carer interview, which ranges from 1 (marked improvement) to 7 (marked worsening). Secondary efficacy outcome measures included behavior, daily function, motor function, and safety. RESULTS The mean change in Mini-Mental State Examination score among participants randomized to latrepirdine (1.5-point improvement) did not differ significantly from that among participants randomized to placebo (1.3-point improvement) (P=.39). Similarly, the distribution of the Clinician Interview-Based Impression of Change, plus carer interview did not differ significantly among those randomized to latrepirdine compared with placebo (P=.84). No significant treatment effects were detected on the secondary efficacy outcome measures. The incidence of adverse events was similar between those randomized to latrepirdine (68.5%) and placebo (68.0%). CONCLUSION In patients with mild to moderate Huntington disease and cognitive impairment, treatment with latrepirdine for 6 months was safe and well tolerated but did not improve cognition or global function relative to placebo. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00920946.

Progression of mild Alzheimer’s disease: knowledge and prediction models required for future treatment strategies

IntroductionKnowledge of longitudinal progression in mild Alzheimer’s disease (AD) is required for the evaluation of disease-modifying therapies. Our aim was to observe the effects of long-term cholinesterase inhibitor (ChEI) therapy in mild AD patients in a routine clinical setting.MethodsThis was a prospective, open-label, non-randomized, multicenter study of ChEI treatment (donepezil, rivastigmine or galantamine) conducted during clinical practice. The 734 mild AD patients (Mini-Mental State Examination (MMSE) score 20 to 26) were assessed at baseline and then semi-annually over three years. Outcome measures included the MMSE, Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), Clinician’s Interview-Based Impression of Change (CIBIC) and Instrumental Activities of Daily Living (IADL) scale.ResultsAfter three years of ChEI therapy, 31% (MMSE) and 33% (ADAS-cog) of the patients showed improved/unchanged cognitive ability, 33% showed improved/unchanged global performance and 14% showed improved/unchanged IADL capacity. Higher mean dose of ChEI and lower educational level were both predictors of more positive longitudinal cognitive and functional outcomes. Older participants and those with a better IADL score at baseline exhibited a slower rate of cognitive decline, whereas younger participants and those with higher cognitive status showed more preserved IADL ability over time. Gender and apolipoprotein E (APOE) genotype showed inconsistent results. Prediction models using the abovementioned scales are presented.ConclusionsIn naturalistic mild AD patients, a marked deterioration in IADL compared with cognitive and global long-term outcomes was observed, indicating the importance of functional assessments during the early stages of the disease. The participants’ time on ChEI treatment before inclusion in studies of new therapies might affect their rate of decline and thus the comparisons of changes in scores between various studies. An increased understanding of expected disease progression in different domains and potential predictors of disease progression is essential for assessment of future therapies in AD.

Long-term rivastigmine treatment in a routine clinical setting

The aim of the study was to observe the effects of long-term rivastigmine treatment in patients with mild to moderate Alzheimer's disease (AD) in a routine clinical setting. This was a prospective, open-label, observational, multicentre, non-randomized study. Outcome measures included the Mini Mental State Examination (MMSE), the Clinician's Interview-Based Impression of Change (CIBIC) and the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog). Of 217 patients initiated into rivastigmine treatment, 62% (n = 135) remained on treatment for 24 months. Most patients droped out due to nursing home placement or side effects. Eighty per cent and 67% of completers exhibited a symptomatic attenuation of cognitive decline (< or = 4-point deterioration) as assessed by using the MMSE and ADAS-cog respectively. Forty-four per cent showed an unchanged/improved CIBIC rating. Over 60% of patients remained on treatment for 2 years in this routine clinical setting. In patients who remained on treatment, rivastigmine appeared to stabilize their condition and prevented or delayed symptomatic decline.

Agent Slows Decline in Mild Alzheimer's

Agent Slows Decline in Mild Alzheimer's

Vagus Nerve Stimulation in Patients With Alzheimer's Disease

Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported. All patients (N = 17) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Responder rates for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) were measured as improvement or absence of decline from baseline. Global change, depressive symptoms, and quality of life were also assessed. Cerebrospinal fluid (CSF) levels for total tau, tau phosphorylated at Thr181 (phosphotau), and Abeta42 were measured by standardized enzyme-linked immunosorbent assay (ELISA). VNS was well tolerated. After 1 year, 7 (41.2%) of 17 patients and 12 (70.6%) of 17 patients improved or did not decline from baseline on the ADAS-cog and MMSE, respectively. Twelve of 17 patients were rated as having no change or some improvement from baseline on the Clinician Interview-Based Impression of Change (CIBIC+). No significant decline in mood, behavior, or quality of life occurred during 1 year of treatment. The median change in CSF tau at 1 year was a reduction of 4.8% (p = .057), with a 5.0% increase in phosphotau (p = .040; N = 14). The results of this study support long-term tolerability of VNS among patients with AD and warrant further investigation.

Olanzapine does not enhance cognition in non-agitated and non-psychotic patients with mild to moderate Alzheimer's dementia

This was an exploratory study of olanzapine as potential treatment for improvement in cognition in patients with Alzheimer's disease without prominent psychobehavioral symptoms. Non-psychotic/non-agitated patients (n = 268) with Alzheimer's disease, who had baseline Mini-Mental State Examination (MMSE) scores of 14-26 were randomized to treatment with olanzapine (2.5 to 7.5 mg/d) or placebo for 26 weeks. The primary objectives were to determine if treatment with olanzapine improved cognition as indexed by the Alzheimer's disease Assessment Scale for Cognition (ADAS-Cog) and the Clinician's Interview-Based Impression of Change (CIBIC) after 26 weeks of therapy. Patients treated with olanzapine vs placebo experienced significant worsening ADAS-Cog scores at weeks 12 (p = 0.03) and 26 (p = 0.004). Changes in CIBIC scores were not significantly different between treatment groups at either assessment. A post hoc analysis revealed that olanzapine-treated patients with more cognitive impairment at baseline (MMSE scores of 14-18) (n = 35) experienced significantly greater deterioration in ADAS-Cog performance than patients in the placebo group (n = 24; p < 0.001); whereas in patients with less cognitive impairment (n = 78, baseline MMSE scores of 23-26) between-group ADAS-Cog changes were not significant. In this 26-week study non-psychotic/non-agitated patients with Alzheimer's disease treated with olanzapine experienced significant worsening of cognition as compared to placebo.

RIVASTIGMINE IN PATIENTS WITH ALZHEIMER'S DISEASE AND CONCURRENT HYPERTENSION

SUMMARYRivastigmine has demonstrated significant benefits in patients with mild to moderate Alzheimer's disease (AD). We aimed to confirm whether rivastigmine was effective in patients with or without concurrent vascular risk factors (VRF), as previously suggested. We chose to stratify the 725 patients involved in an international dose‐ranging study according to the presence of arterial hypertension (a marker of VRF) at baseline. Efficacy in each subgroup was assessed using the ADAS‐cog, a measure of cognitive performance, the Progressive Deterioration Scale (PDS) and the Clinician's Interview‐Based Impression of Change (CIBIC) with caregiver input. Patients receiving rivastigmine 6–12 mg/day showed better outcomes on the ADAS‐cog than those receiving placebo, in both the hypertensive and non‐hypertensive subgroups. Hypertensive patients receiving rivastigmine 6–12 mg/day also showed improvement over those receiving 1–4 mg/day (p=0.023). Rivastigmine 6–12 mg/day also provided better outcomes than placebo on the PDS in the hypertensive (p=0.031) and non‐hypertensive (p=0.035) subgroups. All patients receiving rivastigmine 6–12 mg/day had superior CIBIC‐plus scores than those receiving placebo. There was a trend for lower incidences of nausea and vomiting in rivastigmine‐treated patients with hypertension than in those without hypertension. No cardiac adverse events or drug‐drug interactions were reported. Our data support the hypothesis that rivastigmine provides benefits to patients with or without hypertension, and contribute to the evidence that particular benefits may be observed in those with vascular risk factors.

Qualitative analysis of the clinician interview-based impression of change (Plus): methodological issues and implications for clinical research.

The Clinician Interview-Based Impression of Change, plus carer interview (CIBIC-Plus), is widely used in antidementia drug trials. It comprises Likert scales for disease severity and changes, and written accounts summarizing semistructured interviews evaluating behavior, cognition, and function. Studies using the CIBIC-Plus have focused on the numeric scores to the exclusion of the textual data. Our study explored both sets of data to evaluate whether the CIBIC-Plus written data supported (a) the clinicians' global evaluation of patients' changes during treatment, and (b) the emergence of consistent treatment effects. The global (numeric) scales of change were inconsistently supported by the textual data provided in the CIBIC-Plus. No consistent treatment effects were noted. Methodological problems presently limit the retrospective use of the CIBIC-Plus textual data. Improved standardization of note-taking in the CIBIC-Plus textual data may allow for a better understanding of the typical profiles and clinical importance of changes seen in the course of dementia treatment.

Drs. Raskind and Cyrus Reply

Article AbstractLetter to the Editor Sir: We would like to respond to Dr. Schneider's commentson our article. For regulatory reasons, the Alzheimer's DiseaseAssessment Scale-Cognitive subscale (ADAS-Cog) and ClinicianInterview-Based Impression of Change with Caregiver Input(CIBIC-Plus) are generally the primary outcome measures.It has become increasingly apparent that these primary efficacyvariables do not describe the total symptomatic profile of Alzheimer's disease, and, therefore, the secondary outcomes werereported in our article with equal prominence to scores on theADAS-Cog and the CIBIC-Plus.

Neuropsychophysiological Evaluation of Three Doses of S 12024-2 in Mild-to-Moderate Alzheimerʼs Disease

This study was designed to obtain early evidence that S 12024-2 has potential central pharmacological activity and cognition-enhancing properties in patients with Alzheimer’s disease (AD). This was a single centre, double-blind, crossover study employing three oral doses of S 12024-2 (50, 100, 200mg once daily) and placebo administered over 7 days (Latin square design). 12 outpatients with mild AD (Mini-Mental State Examination scores 18 to 26) were selected according to the National Institute for Neurological and Communication Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association criteria. Clinical and electrophysiological assessments were used as follows: • Clinical assessment was performed using: (a) a semicomputerised battery assessing memory and attention (VDL); (b) the Clinician Interview-Based Impression of Change (CIBIC); (c) an Activities of Daily Living scale filled in by the caregiver • Electrophysiological assessment was performed using Quantitative EEG (qEEG) and Event Related Potentials (ERPs).

Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer's disease

To examine whether estrogen replacement therapy (ERT) affects clinical and cognitive responses to tacrine in women with Alzheimer's disease (AD). A 30-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial of tacrine in which a subgroup of women were receiving ERT prior to randomization. Women with mild to moderate-stage AD, at least 50 years of age, who were enrolled in the previously reported trial. Randomized assignment to placebo or to one of three ascending-dosage regimens of tacrine: maximum dosages of 80 mg/d, 120 mg/d or 160 mg/d. Alzheimer's Disease Assessment Scale-Cognitive Scale (ADASc), Clinician Interview-Based Impression of change (CIBI), Mini-Mental State Examination (MMSE), Caregiver's Impression of Change (CIC). Of 318 women with evaluable data 14.5% were receiving ERT. Women completing the trial taking ERT and tacrine improved more than women not receiving ERT who were randomly assigned to tacrine or to placebo as assessed by the ADASc (p < 0.01), the CIBI (p = 0.02), the CIC (p = 0.006), and the MMSE (p = 0.07). They improved significantly on the ADASc (p = 0.01) using an intent-to-treat analysis. Prior and continuing ERT may enhance response to tacrine in women with AD. Randomized trials are needed.

Parametric Analysis of Tightly Concentrated Ordered-Category Measurements

AbstractThe emphasis currently being placed by the FDA on global clinical judgments recorded on ordered-category rating scales, such as the Clinical Global Impression (CGI) or Clinician Interview-based Impression of Change (CIBIC), has raised serious concerns among industry statisticians about the general acceptability of parametric statistical methods in controlled clinical trials that rely on such measurements for the evaluation of treatment effects. To address these concerns here, simulation methods were used to generate repeated measurements having characteristics of CGI or CIBIC ratings in a randomized parallel-groups design, and repeated measurements analysis of variance (ANOVA), analysis of covariance (ANCOVA), trend tests, and endpoint analyses were applied to the highly discontinuous ordered-category data. The parametric tests of significance were documented to provide appropriate protection against Type I errors and to have power substantially superior to that achieved by dichotomizing outcomes ...