Apathy is the most common neuropsychiatric symptom in Alzheimer’s disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment. In this multicenter, randomized, placebo-controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty-one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)-apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect. Of the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (-3.1, 95% CI -5.7 - -0.5, p = 0.023) or agitation (-3.6, 95% CI -6.1 - -1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (-4.1, 95% CI -6.7 - -1.3, p = 0.004), taking at least one AD medication (-4.0, 95% CI -6.9 - -1.1, p = 0.008), highly educated (-2.1, 95% CI -5.4 – 1.3, p = 0.231), and low functional capacity (-2.6, 95% CI -5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale. Individuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer’s disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 – Operationalizing agitation criteria established by the IPA; 2 – Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 – Using global ratings to define clinically meaningful effects and power studies; 4 – Improving the accuracy of caregiver reports by better training and education of caregivers; 5 – Employing emerging technologies to collect near real-time behavioral data; and 6 – Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.

The objective of this study is to determine if patients with traumatic brain injury (TBI) have similar pathological changes in brain network organization as patients with Alzheimer’s disease (AD) using functional connectome data reconstructed from resting-state fMRI (rsfMRI). To achieve our objective a novel machine learning technique is proposed that uses a top-down reverse engineering approach to identify abnormal network alterations in functional connectome data that are common to patients with AD and TBI. In general, if the proposed machine learning approach classifies a TBI connectome as AD, then this suggests a common network pathology exists in the connectomes of AD and TBI. The advantage of proposed machine learning technique is two-fold: 1) existing longitudinal TBI imaging data is not required, and 2) the potential risk of a TBI patient converting to AD later in life does not require a lengthy and potentially expensive longitudinal imaging study. Experiments are provided that show the AD pathology learned by our connectome-based machine learning technique is able to correctly identify TBI patients with 80% accuracy. In summary, this research may lead to early interventions that can dramatically increase the quality of life for TBI patients who may convert to AD.

IMPORTANCE Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. CONCLUSIONS AND RELEVANCE In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01584440.

Global population aging is pervasive, profound, and enduring, with the projected proportion of older persons reaching nearly 21% in 2050 (UNFPA and Help Age International, 2012). Accordingly, there is an increasing need for geriatric mental health services with the rapid growth of the aging population worldwide (Bragg et al., 2012).

Apathy is a distinct syndrome affecting Alzheimer's disease (AD) patients. Fifty percent of patients suffering from AD will present with apathy. The etiology of apathy in AD is unknown. Confluent information points to a potential association between dopaminergic disruption and apathy in AD. Preliminary data suggests that methylphenidate, a dopamine stimulant, may be effective on apathy in AD. The goal of ADMET was to explore the efficacy and safety of Methylphenidate in the treatment of apathy in AD. ADMET was a multi-site, 6 week, randomized placebo-controlled trial of the efficacy and safety of methylphenidate in mild-to-moderate AD. Patients with a major depressive episode (DSM-IV TR criteria) or psychotic symptoms were excluded. Cognition was assessed using the MMSE. Apathy and other behaviours were assessed using the Apathy Evaluation Scale (AES) and the Neuropsychiatric Inventory (NPI). Efficacy was assessed as the change in score of the AES and the Alzheimer's disease Cooperative Study - Clinical Global Impression of Change (CGIC) scale from baseline to 6 weeks. Secondary efficacy was assessed as the change in Digit Span from baseline to 6 weeks. In total, 60 patients were recruited (62% female, 92% Caucasian, mean (SD) age 76 ± 8 years, mean MMSE 20 ± 5). Subject retention was excellent. Only three participants dropped before week 6. Two of three did not return after baseline and one did not return after the week 2 visit. Recruited participants showed apathy on both the AES (51 ± 12), and NPI Apathy subscale (7.5 ± 2.3). Concomitant medications included cholinesterase inhibitors (72%), memantine (62%) and SSRIs (19%) and 13% of participants had a history of mood disorders. Preliminary results of the primary and secondary measures will be unveiled during this presentation. The treatment of apathy is a major clinical challenge for those treating AD. The results of this study will provide relevant information to clinicians managing this difficult group of patients.

The relationships between genome wide association study-identified and replicated genetic variants associated with Alzheimer's disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. Seven hundred and one AD patients with at least 3 different cognitive evaluations and genotypic information for APOE and 6 genome wide association study-significant single-nucleotide polymorphisms were selected for this study. Mean differences in Global Deterioration Score and Mini Mental State Examination (MMSE) were evaluated using nonparametric tests, general linear model and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor, memantine, or both. Relationships between therapeutic protocols, genetic markers, and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared with GG carriers at the end of the follow-up (MMSE mean difference = -0.57; 95% confidence interval, -1.145 to 0.009; p = 0.047). This observation remained unaltered after covariate adjustments although it did not achieve predefined multiple testing significance threshold. The PICALM single-nucleotide polymorphism also displayed a significant effect protecting against rapid progression during pharmacogenetic assays although its observed effect displayed heterogeneity among AD therapeutic protocols (p = 0.039). None of the studied genetic markers were convincingly linked to AD progression or drug response. However, by using different statistical approaches, the PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes.

Compared to other countries, Japan has a relatively high suicide rate. The suicide rate in 2006 was 23.7 per 100,000, with a particularly high number of suicides among the middle-aged and the elderly. Among Japan’s 47 urban and rural prefectures, Akita prefecture in the Tohoku region has had the highest suicide rate since 1997. In view of this, measures to prevent suicide have been promoted with a clear focus on community-based health promotion for depression. In order to reduce the suicide rate in Akita prefecture, community-based public health intervention through the positive implementation of suicide prevention measures in six towns has been conducted with the cooperation of Akita University. Public awareness raising activities focusing on depression and suicide were conducted. The welfare measures of promoting a sense of purpose among senior citizens and creating a community network were also taken. As a result, the suicide rate in the intervention towns decreased from 70.8 before intervention (1999) to 34.1 after intervention (2004). The suicide rate in the control towns was 47.8 before intervention and 49.1 after intervention. Public health measures emphasizing the population approach of empowerment through specialists and public awareness raising activities regarding depression and suicide prevention aimed at local residents had the effect of increasing mental health literacy concerning depression and suicide, and therefore have the potential to reduce the suicide rate. In conclusion, community-based intervention for depressive elderly with special reference to suicide prevention has the effect of reducing suicide rates in Japanese rural towns.

In this 10-week, double-blind, fixed-dose study, elderly institutionalized patients with dementia and agitation were randomized (3:3:2) to quetiapine 200mg/day, 100mg/day, or placebo. The primary endpoint was change in Positive and Negative Syndrome Scale (PANSS)-Excitement Component (EC) scores at endpoint, analysed using last observation carried forward (LOCF) and observed cases (OC) approaches. Other efficacy measures were the Clinical Global Impression of Change (CGI-C), and response rates (percentage with > or =40% reduction [PANSS-EC]; "much" or "very much improved" [CGI-C]), Neuropsychiatric Inventory-Nursing Home version (NPI-NH), and Cohen-Mansfield Agitation Inventory (CMAI). The key safety measure was incidence of adverse events; change in Mini-Mental State Examination (MMSE) was also assessed. Baseline characteristics of 333 participants (quetiapine 200mg/day, n=117; quetiapine 100mg/day, n=124; placebo, n=92) and completion rates (63-65%) were comparable among groups. Compared with placebo, quetiapine 200mg/day was associated with clinically greater improvements in PANSS-EC (LOCF, p=0.065; OC, p=0.014 [ANCOVA]), CGI-C (LOCF, p=0.017; OC, p=0.002 [ANOVA]), and CGI-C response rates (LOCF, p=0.002; OC, p<0.001 [Chi-square test]). Quetiapine 100mg/day did not differentiate from placebo on these measures. There were no between-group differences in NPI-NH or CMAI. Incidences of cerebrovascular adverse events, postural hypotension, and falls were similar among groups. MMSE did not change in any group. Mortality was numerically higher in the quetiapine groups; rates were not statistically different from placebo. The results of this study suggest that quetiapine 200mg/day was effective and well-tolerated for treating agitation associated with dementia. However, caution should be exercised given the concerns regarding increased mortality with atypical antipsychotics in this vulnerable patient population.

3 J Clin Psychiatry 2006;67 (suppl 10) From the Department of Psychiatry, Medical University of South Carolina, Charleston. This article was supported by an unrestricted educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc. Corresponding author and reprints: Jacobo Mintzer, M.D., Department of Psychiatry, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425 (e-mail: mintzerj@musc.edu). Introduction

A symposium entitled “Challenges in the Management of Psychosis and Alzheimer’s Disease” was held at the 2003 Annual Meeting of the American Association for Geriatric Psychiatry on March 2 in Honolulu, HI. Presenters discussed the treatment of behavioral disturbances in dementia, especially psychosis, and reviewed behavioral management, atypical antipsychotics, and other important therapeutic considerations.