Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial.

OBJECTIVE: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. DESIGN: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. SETTING: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. PARTICIPANTS: Alzheimer's disease patients with clinically significant apathy. MEASUREMENTS: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). RESULTS: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. CONCLUSION: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

BACKGROUND: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. METHODS: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. RESULTS: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). DISCUSSION: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.

Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.

Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments.

BACKGROUND: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. OBJECTIVE: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. METHODS: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. RESULTS: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%). CONCLUSION: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.

VA Video Connect for Clinical Care in Older Adults in a Rural State During the COVID-19 Pandemic: Cross-Sectional Study.

BACKGROUND: The COVID-19 pandemic has accelerated the need for telehealth at home. Although the Department of Veterans Affairs is a leading provider of telehealth, disparities may exist in reaching older veterans living in rural areas. VA Video Connect (VVC) is a video conferencing app that enables veterans to connect with their health care provider via a secure and private session. OBJECTIVE: The aim of this study was to examine the capability and willingness of older veterans to participate in a VVC visit during the COVID-19 pandemic. METHODS: A cross-sectional study was conducted on older veterans (N=118) at the Central Arkansas Veterans Healthcare System. Participants were interviewed over the phone and responses to the following items were recorded: availability of internet, email, and an electronic device with a camera; veterans' willingness to complete an appointment via a VVC visit; and availability of assistance from a caregiver for those who were unable to participate in a VVC visit alone. RESULTS: Participants' mean age was 72.6 (SD 8.3) years, 92% (n=108) were male, 69% (n=81) were Caucasian, 30% (n=35) were African Americans, and 36% (n=42) lived in a rural location. The majority reported having access to the internet (n=93, 77%) and email service (n=83, 70%), but only 56% (n=67) had a camera-equipped device. Overall, 53% (n=63) were willing and capable of participating in a VVC visit. The availability of internet access was significantly lower in rural compared to nonrural participants (P=.045) and in those with or less than a high school education compared to those who pursued higher education (P=.02). Willingness to participate in the VVC visit was significantly lower in rural compared to nonrural participants (P=.03). Of the participants who reported they were able and willing to partake in a VVC visit (n=54), 65% (n=35) opted for VVC and 35% (n=19) preferred a phone visit. In total, 77% (n=27) of the scheduled VVC visits were successful. CONCLUSIONS: Despite advances in technology, and willingness on the part of health care systems, there are some lingering issues with capability and willingness to participate in video telehealth visits, particularly among older adults residing in rural areas.

Association of chronic obstructive pulmonary disease with mild cognitive impairment and dementia.

PURPOSE OF REVIEW: As age expectancy increases, both dementia and chronic obstructive pulmonary disease (COPD) have become more prevalent. Dementia and COPD together, however, occur more commonly than would be predicted from the incidence of either alone, suggesting a link between these two common senescent diseases. The purpose of this article is to review the extant literature and report findings in a clinically meaningful manner. We will look at the level of evidence, the risk factors for co-occurrence of the two diseases and the differential effects upon cognitive domains in the population with dementia and COPD. RECENT FINDINGS: Cognitive impairment in patients with COPD may be 'dose-dependent' with the duration of COPD. Patients with COPD appear to develop nonamnestic mild cognitive impairment (MCI) as opposed to amnestic MCI. Newer studies exploring the impact of oxygen therapy and pulmonary rehabilitation upon cognitive function have reported some positive findings. SUMMARY: Higher prevalence of MCI/dementia is seen in patients with COPD compared with age-matched controls. Imaging findings and dementia/MCI biomarkers provide preliminary evidence for an indirect association of the two conditions. Although no causality can be drawn with the available data, there is some indication that the severity of hypoxemia correlates with the severity of cognitive dysfunction.

Apathy associated with neurocognitive disorders: Recent progress and future directions.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCDs) such as Alzheimer's disease and mild cognitive impairment. Although the definition of apathy is inconsistent in the literature, apathy is primarily defined as a loss of motivation and decreased interest in daily activities. METHODS: The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Syndromes Professional Interest Area (NPS-PIA) Apathy workgroup reviewed the latest research regarding apathy in NCDs. RESULTS: Progress has recently been made in three areas relevant to apathy: (1) phenomenology, including the use of diagnostic criteria and novel instruments for measurement, (2) neurobiology, including neuroimaging, neuropathological and biomarker correlates, and (3) interventions, including pharmacologic, nonpharmacologic, and noninvasive neuromodulatory approaches. DISCUSSION: Recent progress confirms that apathy has a significant impact on those with major NCD and those with mild NCDs. As such, it is an important target for research and intervention.

Psychiatrists' Illustration of Awe in Empathic Listening Assessments: A Pilot Study.

Background "Awe" is typically an inspiring emotional response to perceptually vast stimuli signifying the transcendence beyond all cognitive frames of reference when we encounter the unexpected. Physicians' experience of awe in clinical care interactions has not been studied in an empirical, evidence-based way. We aim to present a focused study of awe in a psychiatrist's empathic listening (EL) assessments and propose an evidence-based framework to study it. Methodology This is an exploratory case series of a psychiatrist's EL interactions (mean duration/x̄ of 46.17 minutes) with six patients (two males and four females) aged 32-72 years (x̄ =54.67, σ = 16.64). Using the method of autoethnography, the verbal and nonverbal aspects of the EL assessments were analyzed and open-coded to generate qualitative data. Results The study revealed that the data in all the case studies could be classed into two thematic groups, namely, mindfulness and transpersonal mindfulness. The emotions of "awe" and "non-agency" were ubiquitous in all six case studies both for the psychiatrist and patients. Conclusions Recognizing the awe and non-agency in EL interaction is essential in conceptualizing the "mindfulness-to-transcendence" framework and the first step toward the evidence-based study of transcendence/metaphysics in phenomenological psychiatry.

Topiramate Monotherapy for Civilian Posttraumatic Stress Disorder: A Controlled Pilot Study.

Objective: To assess the efficacy, safety, and tolerability of topiramate for the treatment of posttraumatic stress disorder (PTSD) in civilians.Methods: This 12-week double-blind, randomized, placebo-controlled study enrolled 72 outpatients (aged 19-64 years) with a DSM-IV-TR diagnosis of non-combat-related PTSD and a score ≥ 50 on the Clinician-Administered PTSD Scale (CAPS). The primary efficacy endpoint, percent change in total CAPS score, and secondary efficacy measures were assessed by analysis of covariance. Safety assessments included monitoring of vital signs, physical examinations, clinical laboratory parameters, electrocardiograms, and adverse events (AEs). The study was conducted from October 2001 to March 2004.Results: The intent-to-treat (ITT) population (N = 68; mean age = 35 years; 87% women; 74% White) showed greater percent reduction in total CAPS scores with topiramate versus placebo (39.5% vs 29.5%), but the difference was not statistically significant (P = .31). Similarly, higher reductions with topiramate versus placebo were seen in the CAPS subscale scores for symptoms of reexperiencing (43.6% vs 34.8%), avoidance/numbing (38.3% vs 30.6%), and hyperarousal (36.6% vs 21.4%). However, these differences were not statistically significant. Six patients in the topiramate arm had a final CAPS score < 20, whereas only 2 in the placebo arm achieved the result (P = .075). The median final topiramate daily dose was 100 mg/d (range, 25-400 mg/d), and mean ± SD treatment duration was 55 ± 32 days, showing the tolerability of the medication. In topiramate-treated patients, treatment-emergent AEs included paresthesia, headache, fatigue, and insomnia; treatment-limiting AEs included influenza-like symptoms, agitation, cognitive problems not otherwise specified, and somnolence. However, a higher rate of AE-related discontinuation was seen in the placebo group than in the treatment group (26% vs 18%).Conclusions: In this 12-week civilian PTSD study, topiramate improved the primary and secondary outcome measures at a higher rate than did placebo, but the difference did not reach statistical significance. Further adequately powered studies may be warranted.Trial Registration: Clinical Trials.gov identifier: NCT00208130.Prim Care Companion CNS Disord 2023;25(5):23m03555. Author affiliations are listed at the end of this article.

Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.

Reversal of SSRI-associated apathy syndrome by discontinuation of therapy.

OBJECTIVE: To report 6 cases of selective serotonin reuptake inhibitor (SSRI)-associated apathy syndrome. CASE SUMMARIES: In all 6 cases, the patient reported loss of motivation while being treated with an SSRI. Loss of motivation was of new onset and temporally associated with the use of the SSRI. A trial of discontinuation of the SSRI was performed in all 6 patients and 2 were started on bupropion while cross-tapering from the SSRI. During the treatment trials, depression and apathy were monitored in all patients. Each case was assessed using the Apathy Evaluation Scale, Clinician version (AES-C), and by evaluating how the patient responded to discontinuation of the SSRI. DISCUSSION: Scores on the AES-C improved significantly in all 6 cases after the SSRI was discontinued. Improvement was also seen in the motivation, novelty, and persistence subdomain scores of the AES-C. A pretreatment AES-C score was available only in the first case. Based on the Naranjo probability scale, there was a probable cause of apathy syndrome with SSRI therapy in the first case and a possible association in the rest of the cases. CONCLUSIONS: In some patients SSRIs may cause an apathy syndrome that can be reversed through discontinuation of the agent. When evaluating patients being treated with an SSRI, clinicians should have a high degree of suspicion and specifically inquire for this iatrogenic form of apathy syndrome.

Cognitive and Functional Abilities in an Older Adult Veteran Before and After Contracting COVID-19.

Background: A 76-year-old male Veteran with a historical diagnosis of mild cognitive impairment was assessed at baseline and follow-up as part of two separate, ongoing studies. He was diagnosed with COVID-19 during the interim. Objective: To report potential effects on cognitive and functional abilities measured before and after contracting COVID-19. Methods: The patient was administered a series of cognitive tests and self-report procedures assessing cognitive, functional, and neuropsychiatric status. Results: Overall, no discernable pattern of cognitive changes between pre-COVID and post-COVID assessments were noted. Only mild increases in agitation, depression, and irritability were noted on a self-report measure. However, this particular subject has relatively ideal psychosocial circumstances in comparison to the typical older adult Veteran male. It is hypothesized that improved psychosocial conditions will result in less negative cognitive and functional outcomes for older adults diagnosed with COVID-19. Conclusion: High levels of resilience, social support, and exercise, coupled with lower levels of perceived stress and loneliness may serve as protective factors against cognitive and functional decline in older adults who contract COVID-19.

Defeated No More: Meaning-Making After Military Sexual Trauma.

INTRODUCTION: Military sexual trauma (MST) has been a concern within our U.S. military for many years. Many interventions have been found to benefit this population, although meaning-based interventions are still lacking in this area. The purpose of this phenomenological study is to understand the meaning-making process and themes that arise for female military veterans as they narrate their experience(s) of MST. MATERIALS AND METHODS: The qualitative study consisted of six female participants, from different areas across the nation, who all reported experiencing MST during their time in service. Their experiences of MST included both sexual harassment and sexual assault. Participants completed a semi-structured interview that was analyzed using an axial coding method to discover the major themes of each participant's interview. The participants discussed the positive and negative aspects of their journey following their MST experience(s). This study's procedures were approved by Adler University's Institutional Review Board. RESULTS: Many found the interview to be a healing experience on their path of post-traumatic growth (PTG). There were eight major themes that arose from the data analysis under the three main domains of (1) creating a work or doing a deed, (2) experiencing something or encountering someone in a way to produce PTG, and (3) altering one's attitude toward unavoidable suffering. The eight themes were as follows: advocacy, adaptive coping, sense of family unit, psychological clarity, meaningful mantra, survivor mentality code, view of self in the world, and resiliency. CONCLUSIONS: All participants endorsed engagement in some type of activity that fell into one of the three major domains identified above. This finding helped highlight the PTG that participants were able to experience through their meaning-making journey. There were several recommendations and study implications that were derived from this research study. With the themes introduced from this study, future treatment planning for individual survivors of MST can be better informed by the utilization of meaning-making techniques. Family and group meaning-based interventions would also be an area of continued exploration for this population. Future implications for practice are also included within this article. Significant limitations of the study include amount of participants, lack of diversity in sample population, qualitative study results, and lack of a more-personal interviewing process.

Veterans Affairs Health Care Provider Perceptions of Virtual Reality: Brief Exploratory Survey.

BACKGROUND: Virtual reality (VR), a simulated experience that can be similar to or completely different from the real world, has become increasingly useful within the psychiatric and medical fields. This VR technology has been applied in medical school trainings, exposure therapy for individuals with posttraumatic stress disorder (PTSD), and reminiscence therapy associated with mood disorders for older adults. Perceptions of VR through the lens of the health care provider require further exploration. VR has grown in popularity; however, this modality continues to be underused in most Veterans Affairs (VA) hospitals. OBJECTIVE: A web-based survey was used to explore health care provider perceptions of immersive VR availability and use for older adults and identify potential barriers for immersive VR use in older adults with cognitive impairment. METHODS: An 8-item web-based survey was developed to obtain health care provider feedback. This survey was disseminated throughout a single Veterans Integrated Services Network (VISN). The VR survey was developed via the Survey Monkey platform and distributed through the secure VA email network. Providers were asked to voluntarily participate in the brief, anonymous survey and offer their perceptions of immersive VR use within their patient population. Survey data were reviewed and interpreted using descriptive statistics. RESULTS: A total of 49 respondents completed the survey over a 15-day period. Of them, 36 respondents (73%) had heard of a VR device, though the majority (n=44, 90%) had never used or prescribed a VR device. Respondents identified several potential barriers to immersive VR use in older adults with cognitive impairment (eg, hearing difficulties, perceptions of technology, cognitive concerns, access to resources, and visual impairment). Despite the barriers identified, providers (n=48, 98%) still reported that they would feel comfortable prescribing immersive VR as an intervention for their patient population. CONCLUSIONS: Survey findings revealed that health care providers within this VISN for VAs have heard of VR, although they may not have actively engaged in its use. Most of the providers reported that they would prescribe the use of an immersive VR intervention for their older adult patients. This key point highlights the desire to implement VR strategies for patient use by their providers. If underlying barriers can be addressed and relatively resolved, this technological intervention has the potential to create substantial breakthroughs in clinical care.