Clinician Interview-Based Impression Research Articles

Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

Donepezil for dementia with Lewy bodies: meta-analysis of multicentre, randomised, double-blind, placebo-controlled phase II, III, and, IV studies.

Current evidence for the management of symptoms associated with dementia with Lewy bodies (DLB) using donepezil is limited. We conducted a meta-analysis of three randomised controlled trials of donepezil in patients with DLB to investigate the overall efficacy of donepezil on Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). A meta-analysis was performed using the data of 312 patients administered placebo or 10 mg donepezil. Overall mean score differences for MMSE, NPI-2, and NPI-10 from baseline to week 12 and their 95% confidence intervals (CI) were estimated. For CIBIC-plus, which was transformed from a seven-point grade to a dichotomous outcome (improvements/no improvements), odds ratio (OR) and its 95% CI were estimated. Random-effects models were used, and heterogeneity was evaluated using the Cochrane's Q test and I2 statistic. Heterogeneity was suspected for NPI-2 (P < 0.05; I2 = 87.2%) and NPI-10 (P < 0.05; I2 = 67.7%) while it was not suspected for MMSE (P = 0.23; I2 = 32.4%) and CIBIC-plus (P = 0.26; I2 = 19.8%). The overall mean MMSE score difference (mean difference: 1.50; 95% CI, 0.67-2.34) and the overall odds of improving CIBIC-plus (OR: 2.20; 95% CI, 1.13-4.26) from baseline to week 12 were higher in the donepezil group than in the placebo group. Results of our meta-analysis indicated overall efficacy of donepezil on cognitive impairment and global clinical status in patients with DLB.

Effect of hyperbaric oxygen on symptoms of dementia in patients with delayed encephalopathy after acute carbon monoxide poisoning.

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most severe complication of carbon monoxide poisoning, which seriously endangers patients' quality of life. This study aims to investigate the efficacy of hyperbaric oxygen (HBO2) on improving dementia symptoms in patients with DEACMP. A retrospective analysis was performed on DEACMP patients, who visited Xiangya Hospital, Central South University from June 2014 to June 2020. Among them, patients who received conventional drug treatment combined with HBO2 treatment were included in an HBO2 group, while those who only received conventional drug treatment were included in a control group. HBO2 was administered once daily. Patients in the HBO2 group received 6 courses of treatment, with each course consisting of 10 sessions. The Hasegawa Dementia Scale (HDS) was used to diagnose dementia, and the Clinical Dementia Rating (CDR) was used to grade the severity of dementia for DEACMP. The Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-Cog), the Functional Activities Questionnaire (FAQ), the Neuropsychiatric Inventory (NPI), and the Clinician's Interview-Based Impression of Change-Plus Caregiver Input (CIBIC-Plus) were performed to assess cognitive function, ability to perform activities of daily living (ADL), behavioral and psychological symptoms, and overall function. The study further analyzed the results of objective examinations related to patients' dementia symptoms, including magnetic resonance imaging detection of white matter lesions and abnormal electroencephalogram (EEG). The changes of the above indicators before and after treatment, as well as the differences between the 2 groups after treatment were compared. There was no significant difference in the HDS score and CDR grading between the 2 groups before treatment (both P>0.05). After treatment, the score of ADAS-Cog, FAQ, NPI, and CIBIC Plus grading of the 2 groups were significantly improved, and the improvement of the above indicators in the HBO2 group was greater than that in the control group (all P<0.05). The effective rate of the HBO2 group in treating DEACMP was significantly higher than that of the control group (89.47% vs 65.87%, P<0.05). The objective examination results (white matter lesions and abnormal EEG) showed that the recovery of patients in the HBO2 group was better than that in the control group. Hyperbaric oxygen can significantly relieve the symptoms of dementia in patients with DEACMP.

Adjunctive transcranial direct current stimulation (tDCS) plus sodium benzoate for the treatment of early-phase Alzheimer's disease: A randomized, double-blind, placebo-controlled trial

Previous studies found that an NMDA receptor (NMDAR) enhancer, sodium benzoate, improved cognitive function of patients with early-phase Alzheimer's disease (AD). Transcranial direct current stimulation (tDCS) induces NMDAR-dependent synaptic plasticity and strengthens cognitive function of AD patients. This study aimed to evaluate efficacy and safety of tDCS plus benzoate in early-phase dementia. In this 24-week randomized, double-blind, placebo-controlled trial, 97 patients with early-phase AD received 10-session tDCS during the first 2 weeks. They then took benzoate or placebo for 24 weeks. We assessed the patients using Alzheimer's disease assessment scale - cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change plus Caregiver Input, Mini Mental Status Examination, Alzheimer's disease Cooperative Study scale for ADL in MCI, and a battery of additional cognitive tests. Forty-seven patients received sodium benzoate, and the other 50 placebo. The two treatment groups didn't differ significantly in ADAS-cog or other measures. Addition of benzoate to tDCS didn't get extra benefit or side effect in this study. For more thoroughly studying the potential of combining tDCS with benzoate in the AD treatment, future research should use other study designs, such as longer-term benzoate treatment, adding benzoate in the middle of tDCS trial sessions, or administering benzoate then tDCS.

Translating clinical notes into quantitative measures-a real-world observation on the response to cholinesterase inhibitors or selective serotonin reuptake inhibitors prescribed to outpatients with dementia using electronic medical records.

Objective: Cholinesterase inhibitors (CEIs) are prescribed for dementia to maintain or improve memory. Selective serotonin reuptake inhibitors (SSRIs) are also prescribed to manage psychiatric symptoms seen in dementia. What proportion of outpatients actually responds to these drugs is still unclear. Our objective was to investigate the responder rates of these medications in an outpatient setting using the electronic medical record (EMR). Methods: We used the Johns Hopkins EMR system to identify patients with dementia who were prescribed a CEI or SSRI for the first time between 2010 and 2021. Treatment effects were assessed through routinely documented clinical notes and free-text entries in which healthcare providers record clinical findings and impressions of patients. Responses were scored using a three-point Likert scale named the NOte-based evaluation method for Treatment Efficacy (NOTE) in addition to the Clinician's Interview-Based Impression of Change Plus caregiver input (CIBIC-plus), a seven-point Likert scale used in clinical trials. To validate NOTE, the relationships between NOTE and CIBIC-plus and between NOTE and change in MMSE (Mini-Mental State Examination) before and after medication were examined. Inter-rater reliability was evaluated using Krippendorff's alpha. The responder rates were calculated. Results: NOTE showed excellent inter-rater reliability and correlated well with CIBIC-plus and changes in MMSEs. Out of 115 CEI cases, 27.0% reported improvement and 34.8% reported stable symptoms in cognition; out of 225 SSRI cases, 69.3% reported an improvement in neuropsychiatric symptoms. Conclusion: NOTE showed high validity in measuring the pharmacotherapy effects based on unstructured clinical entries. Although our real-world observation included various types of dementia, the results were remarkably similar to what was reported in controlled clinical trials of Alzheimer's disease and its related neuropsychiatric symptoms.

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.

Efficacy and safety of 3-n-butylphthalide for the treatment of cognitive impairment: A systematic review and meta-analysis.

BackgroundCurrent evidence for the efficacy of pharmacological treatment in improving cognitive function is absent. Recent studies have reported that 3‐n‐butylphthalide (NBP) has a positive effect on improving cognitive impairment; however, its clinical efficacy and safety is unclear. Therefore, we conducted a meta‐analysis to assess its efficacy and safety for cognitive impairment.MethodsWe systematically searched the PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases, and two reviewers independently screened and extracted the data from included studies. We synthesized the data using the Review Manager Software version 5.3.ResultsWe included six randomized clinical trials (RCTs), encompassing 851 patients with cognitive impairment. The results showed that NBP improved cognitive impairment. Specifically, the clinical efficacy was better than that in the control group, with better performance in improving the Mini‐Mental State Examination and the Montreal Cognitive Assessment scores, while decreasing the Alzheimer's Disease Assessment Scale‐Cognitive subscale and the Clinician's Interview‐Based Impression of Change plus caregiver input scores. There was no significant difference in the incidence of adverse events between both groups.ConclusionThe NBP is effective and safe in improving cognitive impairment; however, more high‐quality RCTs are needed to confirm these findings.

Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia.

Cerebral small vessel disease is a progressivedisease of the brain'sdeep perforating blood vessels.It is usually diagnosed based on lesions seen on brain imaging. Cerebral small vessel disease is a common cause of stroke but can also cause a progressive cognitive decline. As antithrombotic therapy is anestablished treatment for stroke prevention, we sought to determinewhether antithrombotic therapy might also be effective in preventing cognitive decline in people with small vessel disease. To assess the effects of antithrombotic therapy for prevention of cognitive decline in people with small vessel disease on neuroimaging but without dementia. We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Review Group's Specialised Register, and the Cochrane Stroke Group's Specialised Register; the most recent search was on 21 July 2021. We also searched MEDLINE, Embase, four other databases and two trials registries. We searched the reference lists of the articles retrieved from these searches. As trials with a stroke focus may include relevant subgroup data, we complemented these searches with a focussed search of all antithrombotic titles in the Cochrane Stroke Group database. SELECTION CRITERIA: We included randomised controlled trials (RCT) of people with neuroimaging evidence of at least mild cerebral small vessel disease (defined here as white matter hyperintensities, lacunes of presumed vascular origin and subcortical infarcts) but with no evidence of dementia. The trials had to compareantithrombotic therapy of minimum 24 weeks' duration to no antithrombotic therapy (either placebo or treatment as usual), or comparedifferent antithrombotic treatment regimens. Antithrombotic therapy could include antiplatelet agents (as monotherapyor combination therapy), anticoagulants or a combination. Two review authors independently screened all the titlesidentified by the searches. We assessed full texts for eligibility for inclusion according to our prespecified selection criteria, extracted data to a proforma and assessed risk of bias using the Cochrane tool for RCTs. We evaluated the certainty of evidence using GRADE. Due to heterogeneity across included participants, interventions and outcomes of eligible trials, it was not possible to perform meta-analyses. We included threeRCTs (3384 participants). One study investigated the effect of antithrombotic therapy in participants not yet on antithrombotic therapy; two studies investigated the effect of additional antithrombotic therapy, one in a population already taking a single antithrombotic agent and one in a mixed population (participants on an antithrombotic drug and antithrombotic-naive participants). Intervention and follow-up durations varied from 24 weeks to four years. Jia 2016 was a placebo-controlled trial assessing 24 weeks of treatment with DL-3-n-butylphthalide (a compound with multimodal actions, including a putative antiplatelet effect) in 280 Chinese participants with vascular cognitive impairment caused by subcortical ischaemic small vessel disease, but without dementia. There was very low-certainty evidence for a small difference in cognitive test scores favouring treatment with DL-3-n-butylphthalide, as measured by the 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale (adjusted mean difference -1.07, 95% confidence interval (CI) -2.02 to -0.12), but this difference may not be clinically relevant. There was also very low-certainty evidence for greater proportional improvement measured with the Clinician Interview-Based Impression of Change-Plus Caregiver Input (57% with DL-3-n-butylphthalide versus 42% with placebo; P = 0.01), but there was no difference in other measures of cognition (Mini-Mental State Examination and Clinical Dementia Rating) or function. There was no evidence of a difference in adverse events between treatment groups. The SILENCE RCT compared antithrombotic therapy (aspirin) and placebo during four years of treatment in 83 participants with 'silent brain infarcts' who were on no prior antithrombotic therapy. There was very low-certainty evidence for no difference between groups across various measures of cognition and function, rates of stroke or adverse events. The Secondary Prevention of Subcortical Stroke Study (SPS3) compared dual antiplatelet therapy (clopidogrel plus aspirin) to aspirin alone in 3020 participants with recent lacunar stroke. There was low-certainty evidence of no effect on cognitive outcomes as measured by the Cognitive Abilities Screening Instruments (CASI) assessed annually over five years. There was also low-certainty evidence of no difference in the annual incidence of mild cognitive decline between the two treatment groups (9.7% with dual antiplatelet therapy versus 9.9% with aspirin), or the annual stroke recurrence rate(2.5% with dual antiplatelet therapy versus 2.7% with aspirin). Bleeding risk may be higher with dual antiplatelet therapy (hazard ratio (HR) 2.15, 95% CI 1.49 to 3.11; low certainty evidence), but there may be no significant increase in intracerebral bleeding risk(HR 1.52, 95% CI 0.79 to 2.93; low-certainty evidence). None of the included trials assessed the incidence of new dementia. We found no convincing evidence to suggest any clinically relevant cognitive benefit of using antithrombotic therapy in addition tostandard treatment in people with cerebral small vessel disease but without dementia, but there may be an increased bleeding risk with this approach. There was marked heterogeneityacross the trials and the certainty of the evidence was generally poor.

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

&#x0D; &#x0D; &#x0D; &#x0D; Purpose: To compare the effects of propofol and sevoflurane on chronic post-surgical pain and cognitive function after cardiac surgery in Chinese elderly patients.&#x0D; Methods: A total of 200 Chinese patients (aged &gt; 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.&#x0D; Results: Pain severity score was significantly lower in patients treated with propofol than in those who received sevoflurane (6.1 vs 8.4; p &lt; 0.05). Psychological well-being measured using K-10 score was similar in both groups (p &gt;0.05). Similarly, there were no meaningful differences in disability score between the two treatment groups (p &gt; 0.05). The severity of signs and symptoms of dementia were similar at baseline visit (p &gt;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 &gt;0.05). However, incidence of complications (including adverse events) was comparable in both groups (p &gt; 0.05).&#x0D; Conclusion: Propofol produced significantly greater improvement in post-surgical pain and cognitive functions than sevoflurane after cardiac surgery in Chinese elderly patients.&#x0D; &#x0D; &#x0D; &#x0D;

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.

The Clinician's Interview-Based Impression of Change (Plus caregiver input) and goal attainment in two dementia drug trials: Clinical meaningfulness and the initial treatment response.

The Clinician's Interview-Based Impression of Change Plus caregiver input (CIBIC-Plus) has been widely used in dementia drug trials to evaluate cognition, behavior, and function. New trials of symptomatic drugs forecast renewed interest in this measure. To test its clinical meaningfulness, we examined how CIBIC-Plus performed in two cholinesterase inhibitor trials compared to goal attainment scaling Scale (GAS) scores, a patient-reported outcome measure. Net goal attainment was seen for all but one GAS domains in subjects who improved on the CIBIC-Plus. Subjects who improved initially on CIBIC-Plus scores were likely to remain improved across all other outcomes for each trial's duration, except for Disability Assessment for Dementia scores. The initial response to treatment, as assessed by CIBIC-Plus, remained stable for most outcome measures. Even small CIBIC-Plus improvement changes are associated with clinically meaningful change as assessed by GAS. Other tests detect decline better than improvement.

Cerebrolysin for vascular dementia.

Although vascular dementia is the second most common cause of dementia globally, evidence-based treatments are still lacking. Cerebrolysin is a porcine brain-derived preparation that is said to have neurotrophic and neuroprotective activity. In many parts of the world Cerebrolysin, given as a series of daily intravenous infusions, is used as a potential intervention for vascular dementia. A previous Cochrane Review on Cerebrolysin in vascular dementia yielded inconsistent results. We wished to update the review to add new studies from the international literature and employ contemporary methods for appraising the strength of the evidence. This is the first update of a review first published in 2013. Primary: to assess the effect of Cerebrolysin on cognitive function, global function, and all-cause mortality in people living with vascular dementia. Secondary: to assess the adverse effects of Cerebrolysin and to assess the effect of Cerebrolysin on quality of life and caregiver burden. We searched ALOIS, MEDLINE, Embase, PsycINFO, CINAHL, ISI Web of Knowledge, LILACS, the Cochrane Library, ClinicalTrials.gov, and the WHO ICTRP on 16 June 2017, 9 May 2018, and 9 May 2019. We expanded the search by adding four Chinese databases, searched from 1 January 2012 to 19 May 2019. We checked bibliographies of relevant papers identified and contacted pharmaceutical companies, trial authors, and experts in the field to identify any additional published or unpublished data. We included all randomised controlled trials of Cerebrolysin used in people living with vascular dementia. We applied no language restriction. Two review authors independently selected trials for inclusion and evaluated their methodological quality. Data were extracted and analysed using mean differences (MDs) or standardised mean differences (SMDs) with 95% confidence intervals (95% CI) for continuous outcomes. We reported dichotomous outcomes as risk ratio (RR) with 95% CI. We assessed the strength of the available evidence using the GRADE approach. We identified six randomised controlled trials with a total of 597 participants that were eligible for inclusion in the 2013 review. No new studies were eligible for inclusion in this update. Participants in the included studies, where dementia severity was reported, had mild to moderate severity of vascular dementia (four trials). The included studies tested varying doses and duration of Cerebrolysin treatment. Follow-up ranged from 15 days to three years. Five of included studies were conducted in China (three studies), Russia (one study), and Romania (one study), while relevant information of other study was unclear. Where details of funding were available, all studies were supported by the pharmaceutical industry (three studies). Cognitive function was measured using the Mini-Mental State Examination (MMSE) or Alzheimer's Disease Assessment Scale Cognitive Subpart, extended version (ADAS-cog+). Combining the MMSE and ADAS-cog+ data (three studies, 420 people), there was a beneficial effect of Cerebrolysin (SMD 0.36, 95% CI 0.13 to 0.58; very low-quality evidence). Global function was measured by Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC+) or Investigator's Clinical Global Impression (CGI). We assessed response rates on these measures (the proportion of participants with a CIBIC+ score of < 3; or at least moderate improvement of the CGI rating at the last visit). There was a beneficial effect of Cerebrolysin (two studies, 379 participants, RR 2.69, 95% CI 1.82 to 3.98; very low-quality evidence). Only one trial described mortality and reported no deaths. Four studies reported adverse events; data from two studies (379 people) were in a format that permitted meta-analysis, and there was no difference in rates of adverse effects (RR 0.91, 95% CI 0.29 to 2.85; very low-quality evidence). No studies reported on quality of life or caregiver burden. Courses of intravenous Cerebrolysin improved cognition and general function in people living with vascular dementia, with no suggestion of adverse effects. However, these data are not definitive. Our analyses were limited by heterogeneity, and the included papers had high risk of bias. If there are benefits of Cerebrolysin, the effects may be too small to be clinically meaningful. There have been no new studies of Cerebrolysin in vascular dementia since the last Cochrane Review. Cerebrolysin continues to be used and promoted as a treatment for vascular dementia, but the supporting evidence base is weak. Adequately powered, methodologically robust trials are needed to properly assess the effects of Cerebrolysin in vascular dementia.

A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2A CLINICAL TRIAL OF NA-831 IN PATIENTS WITH MCI AND EARLY ONSET ALZHEIMER’S DISEASE

Preclinical experiments indicate that NA-831 is an endogenous small molecule that exhibits neuroprotection, neurogenesis, and cognitive protective properties across a range of disease models. NA-831 has been shown to be safe and well tolerated in healthy volunteers. A randomized clinical trial of NA-831 was performed in a total of 56 patients: 32 Alzheimer patients with MCI, and 24 patients with early onset of Alzheimer's disease. The patients with MCI received 10 mg of NA-831 or placebo orally per day. The patients with early onset of Alzheimer's disease received 30 mg of NA-831 or placebo orally per day. Randomization was performed by a centralized Interactive Voice and Web Response System. The study was conducted in accordance with the Declaration of Helsinki and ICH and GCP guidelines. All patients provided written informed consent. Inclusion criteria included: (a) male or female, at 55–80 years of age at screening, (b) For MCI patients, MMSE score ≥20. For patients with early onset Alzheimer's disease, MMSE score> 17 (d) Center for Epidemiological Studies-Depression (CES-D) score <27. Patients were randomly assigned to NA-831 at a daily dosage of 10 mg- 30 mg or matched placebo (1:1). The primary outcome measures were the changes in ADAS-cog, brief cognitive rating scale (BCRS) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 48 weeks. Based on the BCRS, the effects of NA-831 were apparent after 12 weeks of treatment (p=0.001), with the significant improvement in: fatigue, anxiety, irritability, affective lability, disturbance to waking, daytime drowsiness, headache, and nocturnal sleep. NA-831 showed a significant improvement for patients with mild and moderate AD with the ADAS-Cog score changed of an average of 3.9 as compared to the placebo (NA-831 change −4.7 vs. placebo −8.6; P = 0.001; ITT). CIBIC-Plus showed 79.3% vs. 21.7 % patients improved; P = 0.01; ITT). NA-831 was well-tolerated at high dosage up to 50 mg per day. No adverse effects were reported. Over the 48 week treatment period, NA-831 was effective for improving cognitive and global functioning in patients with mild cognitive impairment. As an endogenous compound, NA-831 is well-tolerated and has excellent safety profile.

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.

Memantine ER Maintains Patient Response in Moderate to Severe Alzheimer's Disease: Post Hoc Analyses From a Randomized, Controlled, Clinical Trial of Patients Treated With Cholinesterase Inhibitors.

Memantine extended release (ER) significantly outperformed placebo on co-primary endpoints of Clinician's Interview-based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline to endpoint changes on the Severe Impairment Battery (SIB) in a 24-week, randomized trial (NCT00322153) in patients with moderate to severe Alzheimer's disease taking a cholinesterase inhibitor (ChEI). A post hoc analysis compared patients receiving memantine ER/ChEI to placebo/ChEI for time to onset of response and if the response was maintained (achieving improvement at weeks 8, 12, or 18 and maintaining through endpoint/week 24) on the SIB, the Neuropsychiatric Inventory (NPI), CIBIC-Plus, and Activities of Daily Living (ADL) using Fisher exact test. A second post hoc analysis compared percentages of patients for all possible combinations of 2 to 4 assessments with either no decline or clinically notable response using Wald χ. Significantly greater percentages of memantine ER/ChEI patients achieved an early response that was maintained on SIB, NPI, and CIBIC-Plus (P<0.05) versus placebo/ChEI. Significantly greater percentages of memantine ER/ChEI-treated patients achieved and maintained a clinically notable response on ADL/NPI, SIB/ADL/NPI, and SIB/ADL/CIBIC-Plus, compared with placebo/ChEI (P<0.05). Memantine ER results in early, maintained improvement in patients with moderate to severe Alzheimer's disease concurrently taking ChEIs, compared with cholinesterase treatment alone.

Phase II Clinical Trial of Nicotinamide for the Treatment of Mild to Moderate Alzheimer's Disease

Disease-modifying treatments for Alzheimer's disease (AD) are currently unavailable and are the focus of an intensive research effort. We found vitamin B3, nicotinamide (NA), to significantly reduce pathology and improve behavior in AD transgenic mice. These results led us to conduct a double-blind, placebo-controlled randomized clinical trial of NA in mild to moderate AD.Following randomization, subjects received either NA (n = 15, 1500 mg twice daily) or placebo (n = 16) for 24 weeks. A battery of outcome measures were obtained at baseline and 6- week intervals and included the AD Assessment Scale-Cognitive Subscale, Clinician's Interview-Based Impression of Change Plus Caregiver Input, AD Cooperative Study-Activities of Daily Living Scale, and Clinical Dementia Rating Scale.

Efficacy and Safety of Donepezil in Chinese Patients with Severe Alzheimer's Disease: A Randomized Controlled Trial.

Donepezil has been used worldwide for the treatment of severe Alzheimer's disease (AD). Whether it is also appropriate for severe AD in Chinese patients remains unknown. To determine whether donepezil is effective and tolerable for Chinese patients with severe AD. The present study was a 24-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study conducted at 38 investigational hospitals in China. Patients with severe AD were enrolled in this trial. Patients were randomly assigned in a 1:1 ratio to receive either donepezil or placebo (5 mg for 6 weeks and10 mg for the remaining 18 weeks). The efficacy for donepezil were evaluated by the SIB, the Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-plus) and the MMSE. Safety parameters were monitored throughout. A total of 313 patients included the donepezil (n = 157) and the placebo groups (n = 156). Donepezil group improved more in SIB scores (least squares [LS] mean difference: 4.8, 95% CI 1.56 to 8.08, p = 0.004) and CIBIC-plus scores (drug-placebo difference: -0.4, 95% CI -0.66 to 0.03, p = 0.04) than placebo groups at Week 24. The MMSE scores between drug and placebo groups did not differ significantly. Twenty-nine patients with serious adverse events (SAEs) were reported in donepezil (n = 11) and placebo groups (n = 18) (p = 0.08). Most SAEs were not considered drug-related. Donepezil for 24 weeks was more effective than placebo and showed good safety and tolerability in Chinese patients with severe AD. This study supports utility of the drug in severe stages of AD in the Chinese population.

Comprehensive, Individualized, Person-Centered Management of Community-Residing Persons with Moderate-to-Severe Alzheimer Disease: A Randomized Controlled Trial

Background/Aims: The aim was to examine added benefits of a Comprehensive, Individualized, Person-Centered Management (CI-PCM) program to memantine treatment. Methods: This was a 28-week, clinician-blinded, randomized, controlled, parallel-group study, with a similar study population, similar eligibility criteria, and a similar design to the memantine pivotal trial of Reisberg et al. [N Engl J Med 2003;348:1333-1341]. Twenty eligible community-residing Alzheimer disease (AD) subject-caregiver dyads were randomized to the CI-PCM program (n = 10) or to usual community care (n = 10). Primary outcomes were the New York University Clinician's Interview-Based Impression of Change Plus Caregiver Input (NYU-CIBIC-Plus), assessed by one clinician set, and an activities of daily living inventory, assessed by a separate clinician set at baseline and at weeks 4, 12, and 28. Results: Primary outcomes showed significant benefits of the CI-PCM program at all post-baseline evaluations. Improvement on the NYU-CIBIC-Plus in the management group at 28 weeks was 2.9 points over the comparator group. The memantine 2003 trial showed an improvement of 0.3 points on this global measure in memantine-treated versus placebo-randomized subjects at 28 weeks. Hence, globally, the management program intervention benefits were 967% greater than memantine treatment alone. Conclusion: These results are approximately 10 times those usually observed with both nonpharmacological and pharmacological treatments and indicate substantial benefits with the management program for advanced AD persons.

Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias.

(Reprinted with permission from American Psychiatric Association, http://psychiatryonline.org/guidelines).

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.