Methylphenidate for Apathy in Community-Dwelling Older Veterans With Mild Alzheimer’s Disease: A Double-Blind, Randomized, Placebo-Controlled Trial

Padala, Prasad R.; Padala, Kalpana P.; Lensing, Shelly; Ramirez, Daniel A.; Monga, Varun; Bopp, Melinda M.; Roberson, Paula K.; Dennis, Richard A.; Petty, Frederick; Sullivan, Dennis H.; Burke, William J.

doi:10.1176/appi.ajp.2017.17030316

Cited by 91 publications

(83 citation statements)

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“…In trials investigating the use of methylphenidate in older patients with AD (mean age > 75), side effects were modest. However, symptomatic cardiovascular disease was an exclusion criterion in these trials [8,9]. Follow-up studies with cardiovascular monitoring are necessary to investigate whether repeated/prolonged methylphenidate administration is safe in older patients with cardiovascular disease before implemented in a clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…Methylphenidate may improve executive functioning by increasing norepinephrine and dopamine concentrations in the synaptic cleft [6]. While some studies in patients with dementia due to Alzheimer's disease (AD) have suggested an effect of methylphenidate on global cognition and on attention [7][8][9][10], other studies have not consistently supported the results [11]. In patients with VCI, only 1 small older open label longitudinal study in 15 patients with dementia found that methylphenidate slightly improved scores on the Mini-Mental State Examination (MMSE) [12].…”

Section: Introductionmentioning

confidence: 99%

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Methylphenidate and galantamine in patients with vascular cognitive impairment–the proof-of-principle study STREAM-VCI

et al. 2020

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Background: To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients. Methods: STREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) ≥ 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart®, a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance. Results: The study population had a mean age of 67 ± 8 years and MMSE 26 ± 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference − 0.84; 95% CI − 1.65, − 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients. Conclusions: In this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen. Trial registration: http://www.clinicaltrials.gov. Registration number: NCT02098824. Registration date: March 28, 2014.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methylphenidate and galantamine in patients with vascular cognitive impairment–the proof-of-principle study STREAM-VCI

et al. 2020

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“…apathy. A recent double-blind, randomized, placebo-controlled trial (DBRPCT) of methylphenidate (n = 60), a psychostimulant, showed that this drug improved the apathy evaluation scale-clinician version (AES-C) [8] score in patients with AD as compared with a placebo [9]. However, another DBRPCT of methylphenidate (n = 60), which used the apathy evaluation scale-informant (AES-I) [10], did not show this effect in patients with AD [11].…”

Section: Efficacy and Safety Of Psychostimulants For Alzheimer's Disementioning

confidence: 99%

“…The outcomes of our study were apathy (primary) scale score (i. e., frontal systems behavior scale apathy [14] from 1 study [15], AES-I from 2 studies [11,16], and AES-C from 1 study [9]), mini-mental state examination (MMSE) score [17], instrumental activities of daily living scale (IADL) score [18], Zarit burden interview [19] score, all-cause discontinuation rate, discontinuation due to adverse events, and incidence of individual adverse event. For evaluating apathy, 1 study [15] used frontal systems behavior scale apathy, 2 studies [11,16] used both AES-I and neuropsychiatric inventory (NPI) apathy score [20], and another study [9] used AES-C. There were 2 studies using the NPI apathy score.…”

Section: Data Sources Studies Sections and Data Extractionmentioning

confidence: 99%

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Efficacy and Safety of Psychostimulants for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2020

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Introduction Several reports of the effectiveness of the use of psychostimulants for the treatment of Alzheimer’s disease (AD) are available. Methods A systematic review and meta-analysis was conducted including double-blind, randomized, placebo-controlled trials. Outcomes were the improvement of apathy scales score (primary), mini-mental state examination (MMSE) score, activities of daily living scale score, Zarit burden interview score, all-cause discontinuation, discontinuation due to adverse events, and incidence of at least 1 adverse event. Results Three methylphenidate studies and 1 modaﬁnil study were identified (n=156). Results from combined psychostimulants were superior to placebo in the improvement of apathy scales score (standardized mean differences [SMD]=−0.63 (−1.22, −0.04), p=0.04, all studies) and the MMSE score (SMD=−0.58 (−1.14, −0.02), p=0.04, 3 methylphenidate studies). The modaﬁnil study was excluded from the meta-analysis for the improvement of apathy scales score; therefore, the effect size increased (SMD=−0.82 (−1.43, −0.20), p=0.009). However, no significant differences were observed in terms of other outcomes, including safety outcomes between the treatment groups. Discussion Methylphenidate would be effective in treating apathy and cognitive impairment in AD patients.

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Bupropion for the Treatment of Apathy in Alzheimer Disease

et al. 2020

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IMPORTANCE Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed. OBJECTIVE To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. DESIGN, SETTING, AND PARTICIPANTS This 12-week, multicenter, double-blind, placebocontrolled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. INTERVENTIONS Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. MAIN OUTCOMES AND MEASURES Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. RESULTS A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI,-0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change,-1.66; 95% CI,-3.01 to-0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change,-2.92; 95% CI,-5.89 to 0.06; P = .05) and cognition (mean change,-0.27; 95% CI,-3.26 to (continued) Key Points Question Is bupropion an effective and safe treatment for apathy in nondepressed patients with dementia of Alzheimer type? Findings In this 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial, 54 patients received bupropion and 54 received placebo. The mean change in the Apathy Evaluation Scale-Clinician Version score was not statistically significant between the treatment groups....

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Methylphenidate for Apathy in Community-Dwelling Older Veterans With Mild Alzheimer’s Disease: A Double-Blind, Randomized, Placebo-Controlled Trial

Abstract: Methylphenidate improved apathy in a group of community-dwelling veterans with mild Alzheimer's disease. Methylphenidate also improved cognition, functional status, caregiver burden, CGI scores, and depression.

Cited by 91 publications

References 35 publications

Methylphenidate and galantamine in patients with vascular cognitive impairment–the proof-of-principle study STREAM-VCI

Methylphenidate and galantamine in patients with vascular cognitive impairment–the proof-of-principle study STREAM-VCI

Efficacy and Safety of Psychostimulants for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Bupropion for the Treatment of Apathy in Alzheimer Disease

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