Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial

Jacobo Mintzer; Krista L Lanctôt; Roberta W Scherer; Paul B Rosenberg; Nathan Herrmann; Christopher H van Dyck; Prasad R Padala; Olga Brawman-Mintzer; Anton P Porsteinsson; Alan J Lerner; Suzanne Craft; Allan I Levey; William Burke; Jamie Perin; David Shade

doi:10.1001/jamaneurol.2021.3356

. 2021 Sep 27;78(11):1–9. doi: 10.1001/jamaneurol.2021.3356

Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease

The ADMET 2 Randomized Clinical Trial

Jacobo Mintzer ^1,^✉, Krista L Lanctôt ², Roberta W Scherer ³, Paul B Rosenberg ⁴, Nathan Herrmann ², Christopher H van Dyck ⁵, Prasad R Padala ⁶, Olga Brawman-Mintzer ¹, Anton P Porsteinsson ⁷, Alan J Lerner ⁸, Suzanne Craft ⁹, Allan I Levey ¹⁰, William Burke ¹¹, Jamie Perin ³, David Shade ³, for the ADMET 2 Research Group

¹Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston

²Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada

³Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

⁴Johns Hopkins University School of Medicine, Baltimore, Maryland

⁵Yale School of Medicine, New Haven, Connecticut

⁶Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock

⁷University of Rochester School of Medicine and Dentistry, Rochester, New York

⁸University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

⁹Wake Forest University, Winston-Salem, North Carolina

¹⁰Emory Goizueta Alzheimer’s Disease Research Center, Atlanta, Georgia

¹¹Banner Alzheimer’s Institute, Phoenix, Arizona

Group Information: The ADMET 2 Research Group members are listed in Supplement 3.

^✉

Corresponding Author: Jacobo Mintzer, MD, MBA, South Carolina Institute for Brain Health, a Division of the Lowcountry Center for Veterans Research (VA-affiliated 501c3), Ralph H. Johnson VA Medical Center, 22 Westedge St, Ste 410, Charleston, SC 29403 (mintzerj@musc.edu).

Accepted for Publication: June 17, 2021.

Published Online: September 27, 2021. doi:10.1001/jamaneurol.2021.3356

Author Contributions: Drs Perrin and Shade had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Mintzer and Lanctôt both have equal contributions to the development of this manuscript.

Concept and design: Mintzer, Lanctôt, Scherer, Rosenberg, Herrmann, Padala, Porsteinsson, Lerner, Shade.

Acquisition, analysis, or interpretation of data: Mintzer, Rosenberg, Herrmann, van Dyck, Padala, Brawman-Mintzer, Porsteinsson, Lerner, Craft, Levey, Burke, Perin, Shade.

Drafting of the manuscript: Mintzer, Lanctôt, Scherer, Rosenberg, Herrmann, Padala, Brawman-Mintzer, Lerner, Shade.

Critical revision of the manuscript for important intellectual content: Mintzer, Lanctôt, Rosenberg, Herrmann, van Dyck, Padala, Porsteinsson, Lerner, Craft, Levey, Burke, Perin, Shade.

Statistical analysis: Lerner, Perin, Shade.

Obtained funding: Mintzer, Lanctôt, Scherer, Rosenberg, Herrmann.

Administrative, technical, or material support: Mintzer, Lanctôt, Scherer, Rosenberg, Herrmann, van Dyck, Padala, Brawman-Mintzer, Porsteinsson, Lerner, Shade.

Supervision: Mintzer, Lanctôt, Scherer, Rosenberg, van Dyck, Porsteinsson, Shade.

Conflict of Interest Disclosures: Dr Mintzer reported being an advisor for Praxis Bioresearch and Cerevel Therapeutics outside the submitted work. Dr Lanctôt reported grants from the National Institutes of Health during the conduct of the study and personal fees for serving on the advisory boards of BioXcel Therapeutics, Cerevel Therapeutics, Praxis, Eisai, and Kondor Pharma outside the submitted work. Dr Scherer reported grants from Johns Hopkins University during the conduct of the study. Dr Rosenberg reported grants from National Institute on Aging during the conduct of the study; grants from Eli Lilly and Company, Vaccinex, Functional Neuromodulation, Alzheimer’s Therapeutic Research Institute, Alzheimer’s Clinical Trials Consortium, and Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease outside the submitted work; and personal fees for consulting for Gerson Lehrman Group, SVB Leerink, Cerevel Therapeutics, Cerevance, Acadia Pharmaceuticals, BioXcel Therapeutics, Sunovion, and the US Food and Drug Administration outside the submitted work. Dr Herrmann reported grants from the National Institute on Aging during the conduct of the study. Dr van Dyck reported grants from the National Institute on Aging during the conduct of the study; personal fees for consulting for Roche, Eisai, and Ono Pharmaceutical outside the submitted work; and grants from Roche, Eisai, Eli Lilly and Company, Biogen, Biohaven Pharmaceuticals, Novartis, Janssen, Genentech, and Merck outside the submitted work. Dr Padala reported grants from Office of Research Development, Department of Veterans Affairs and National Institutes of Health during the conduct of the study. Dr Brawman-Mintzer reported grants from the National Institute on Aging during the conduct of the study. Dr Porsteinsson reported grants from the National Institutes of Health during the conduct of the study; personal fees for serving on the data and safety monitoring boards of Acadia Pharmaceuticals, Cadent Therapeutics, Functional Neuromodulation, Novartis, and Syneos outside the submitted work; grants from Avanir Pharmaceuticals, Biogen, Eisai, Eli Lilly and Company, Genentech/Roche, Biohaven, Athira, Alector, Vaccinex, and Novartis outside the submitted work; and personal fees from Avanir, Biogen, Eisai, Alzheon, MapLight Therapeutics, Premier Healthcare Solutions, Sunovion, IQVIA, and Ono Pharmaceuticals outside the submitted work. No other disclosures were reported.

Funding/Support: Funding was provided by the National Institute on Aging (grant R01 AG046543).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The ADMET 2 Research Group members are listed in Supplement 3.

Data Sharing Statement: See Supplement 4.

Meeting Presentation: Data were presented during the Alzheimer’s Association International Conference; July 29, 2021; virtual.

Additional Contributions: We acknowledge the dedication of all study participants and caregivers who contributed to this trial and the many contributions of all members of the ADMET 2 Research Group,²⁰ as previously described.

^✉

Corresponding author.

PMCID: PMC8477302 PMID: 34570180

This randomized clinical trial measures whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.

Key Points

Question

Does methylphenidate decrease apathy in individuals with Alzheimer disease?

Findings

In this randomized clinical trial of 200 participants, methylphenidate vs placebo was found to be safe and was associated with a decrease in apathy symptoms as measured by the Neuropsychiatric Inventory within 2 months that was sustained for 6 months.

Meaning

Methylphenidate may be useful for the treatment of apathy in individuals with Alzheimer disease, which can reduce symptoms and caregiver burden.

Abstract

Importance

Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.

Objective

To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.

Design, Setting, and participants

This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included.

Interventions

Ten milligrams of methylphenidate, twice daily, vs matching placebo.

Main Outcomes and Measures

The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life.

Results

Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, −1.25; 95% CI, −2.03 to −0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups.

Conclusions and Relevance

This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease.

Trial Registration

ClinicalTrials.gov Identifier: NCT02346201

Introduction

Apathy is one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease (AD).^1,2 Apathy is defined as diminished will and initiative, lack of interest in activities, and limited affective response to positive or negative events³ that is present for at least 4 weeks.⁴ Apathy affects up to 71% of people with dementia and results in excess disability.⁵

Apathy is associated with caregiver burden and distress,⁶ increased service utilization, accelerated institutionalization,⁷ increased mortality risk,^8,9,10 and financial burden.^8,9,10,11,12 No treatments are proven to treat apathy in AD, but catecholaminergic agents such as methylphenidate hold promise.^13,14,15 Methylphenidate has been one of the most studied catecholaminergic compounds in older adults and has a good safety profile¹⁶ with 2 trials showing preliminary efficacy in apathy in AD. The Apathy in Dementia Methylphenidate Trial (ADMET) found that methylphenidate treatment of apathy in AD was associated with significant improvement in 2 of 3 efficacy outcomes, suggesting an improvement in global cognition and minimal adverse effects.^17,18 The second study¹⁹ showed efficacy in all primary and secondary outcome measures as well as minimal adverse events. However, both trials were small and of short duration (6 and 12 weeks, respectively). To clarify the clinical efficacy of methylphenidate for apathy in AD more precisely, we conducted a larger, longer trial with more robust measures: the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), a phase 3, placebo-controlled, masked, 6-month, multicenter randomized clinical trial involving 200 participants with apathy and AD.

Methods

Participants

The design and rationale of ADMET 2 were recently published.²⁰ The trial protocol is available in Supplement 1. Briefly, participants were recruited at 10 clinical centers (9 US clinics and 1 Canadian clinic) specializing in dementia care where they or their legally authorized representatives and the primary caregiver for the participant provided informed consent. The study adhered to the Declaration of Helsinki²¹ and was approved by the ethical review boards of each site. Participants were enrolled from May 2016 to December 2019 with the final visit in July 2020.

Participants included individuals of all race and ethnic groups as self-defined by the participant or their study partner. As required by National Institutes of Health policy, we conducted valid subgroup analyses of the primary and adverse event outcomes by sex and race and ethnicity to determine if there are possible differences (ie, interactions) in treatment effects.

Inclusion criteria included (1) diagnosis of possible or probable AD, using criteria from the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association²²; (2) Mini-Mental State Examination²³ scores between 10 and 28; (3) clinically significant apathy very frequently or frequently/often with a severity of moderate or marked for at least 4 weeks on the Neuropsychiatric Inventory (NPI)²⁴; and (4) availability of a caregiver, who spent more than 10 hours a week with the potential participant. Exclusion criteria were (1) individuals experiencing a current or previously diagnosed major depressive episode by the Diagnostic and Statistical Manual of Mental Disorder; (2) clinically significant agitation/aggression, delusions, or hallucinations very frequently, frequently with severity of moderate, or marked on the NPI; (3) change in AD medication within the preceding 30 days; (4) change in use of antidepressants (except for trazodone for sleeping difficulties), lorazepam (except for sleeping difficulties), or benzodiazepines within preceding 30 days or within 5 half-lives of drug; (5) past failure of methylphenidate treatment; (6) current medication precluding safe use of methylphenidate; (7) current uncontrolled medical condition for which methylphenidate is contraindicated, including central nervous system abnormalities, hyperthyroidism, closed angle glaucoma, or cardiovascular or cerebrovascular abnormality; and (8) significant unintentional weight loss within previous 3 months.

Participants were randomized to methylphenidate or placebo in a 1:1 ratio using a randomization schedule stratified by clinical center with permuted length blocks and generated using a documented program in SAS statistical software version 9.2 (SAS Institute). Clinic staff obtained treatment assignments centrally using a web-based data system.

Intervention

Study drug was supplied as identical-appearing capsules containing either 5 mg of generic methylphenidate or placebo (cellulose) and dosed as 1 capsule twice a day (10 mg/d in the methylphenidate group) for 3 days, followed by 2 capsules twice a day (20 mg/d) for the remainder of the study. Study physicians could reduce the dose in the event of participant adverse events. Participants continued receiving all concomitant medications. All study partners and participants received a standardized psychosocial intervention, composed of a 20- to 30-minute counseling session at each visit, educational materials, and 24-hour availability of study staff for crisis management. In-person follow-up visits took place monthly for 6 months. Telephone contacts occurred at days 15, 45, and 75 after randomization. Virtual or telephone visits were allowed when COVID-19 precluded safe in-person visits.

Outcomes

Efficacy Outcomes

Two coprimary outcomes were prespecified: (1) mean change in the NPI apathy score from baseline to 6 months and (2) odds of improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC)²⁵ between baseline and 6 months, with attainment of significance for either outcome, signaling an efficacious treatment. A significant result for either primary outcome would indicate treatment efficacy. Secondary outcomes included change between baseline and 6 months in the Dementia Apathy Interview and Rating,²⁶ a 16-item, informant rated scale that evaluates the change in motivation, engagement, and emotional response since disease onset. Higher scores indicate more apathy. Other outcomes included presence of adverse events and change in cognition and/or quality of life, described in detail below.

The NPI, administered as a structured interview with the caregiver, assessed the presence and severity of 12 neuropsychiatric symptoms, including apathy. Scores were calculated by multiplying frequency (range, 0-4) and severity (range, 0-3); higher scores indicate more frequent and/or severe symptoms. The ADCS-CGIC, administered by an independent clinician, was used to assess clinically meaningful change in apathy. Ratings were based on a 7-point Likert-type scale (ranging from very much worse to very much improved); a rating of 4 was equivalent to no change.

Cognitive and Other Outcomes

Cognitive tests were performed at baseline and at 2, 4, and 6 months and included the Mini-Mental State Examination,²³ Hopkins Verbal Learning Test,²⁷ Wechsler Adult Intelligence Scale—Revised Digit Span,²⁸ Trail Making Test parts A and B,²⁹ action verbal fluency test from the Parkinson’s Disease—Cognitive Rating Scale,³⁰ Category Fluency Task—Animal Naming,³¹ and the Short Boston Naming³² as previously described.²⁰ Other outcomes included the Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale,³³ Dependence Scale,³⁴ EuroQol 5-dimension 5-level,³⁵ and the Resource Utilization in Dementia—Lite.³⁶

Adverse Events and Safety Monitoring

Adverse events data were collected by systematic, close-ended questions for known or expected adverse events of methylphenidate, open-ended questions for unexpected adverse events, and results of vital signs, electrolyte panels, and electrocardiogram results. Weight loss of 7% or more from baseline was considered an adverse event. Serious adverse events were defined as adverse events leading to hospitalization, emergency department visit, or death. A 3-person data safety and monitoring committee reviewed accumulating, unmasked data on the safety and efficacy of methylphenidate compared with placebo. An interim analysis was reviewed when half of the study participants had been enrolled. There were no formal stopping rules or reported P values for this analysis.

Statistical Methods

Based on the difference in NPI apathy change scores (1.8 points) and SD (3.2) previously observed,¹⁸ a sample size of 200 provided for greater than 90% power to detect a difference of 1.8 points in change on the NPI apathy subscale with 15% loss of participants. The power and sample size for the ADCS-CGIC outcome was determined using the method of Whitehead³⁷ for proportional odds logistic regression and values from ADMET of −5 for moderate and −3 for minimal improvement. Assuming an odds ratio for better ratings in methylphenidate of 2.75 and 200 participants, the study would have greater than 85% power with 15% losses. We assumed a type I error rate of 0.025 to preserve an overall type I error rate of 0.05 over both primary comparisons.

We used means, SDs, medians, and proportions to describe baseline characteristics of the study participants following verification of symmetrical distribution of continuous variables. The assessment of efficacy was based on an intention-to-treat analysis of the 2 primary outcomes: mean change in the NPI score from baseline to 6 months and change in rating on the ADCS-CGIC at 6 months.

The primary comparison for the first coprimary outcome, difference in mean change from baseline to month 6, was evaluated longitudinally using a linear mixed-effects model with random intercept for each participant and adjusted for clinic, age, sex, and diabetes. The primary comparison for the second coprimary outcome was a proportional odds logistic regression implemented by the ‘popower’ in the Hmisc package in R comparing the ADCS-CGIC ratings of change at month 6 between treatment groups. We also used a generalized mixed model to evaluate the mean change in the ratings between the treatment groups from baseline to month 6. Prespecified subgroup analyses included comparison of clinics located in the United States vs Canada and valid analyses by sex and race and ethnicity as required by National Institutes of Health policy. We used Kaplan-Meier estimates to determine the timeline associated with the incident absence of any apathy symptoms as measured using the NPI. Statistical analyses were performed using SAS statistical software version 9.2 (SAS Institute) and R version 3.16.1 (R Foundation). All P values were 2-sided and P < .05 was used as the threshold for statistical significance.

Results

Of 307 persons screened, 52 did not pass the screen and 55 were not eligible following the baseline eligibility visit. Of the 200 individuals randomized, 99 were assigned to methylphenidate and 101 to placebo (Figure 1). Ten study participants in the methylphenidate group and 7 in the placebo group withdrew from the study; missed visits occurred throughout the study, with some delayed or missed owing to COVID-19. The intention-to-treat analysis at month 6 included 89 participants in the methylphenidate and 92 in the placebo group. Baseline data were missing for 1 participant.

Figure 1. — AD indicates Alzheimer disease.

By participant/caregiver self-report, 69 participants (78%) in the methylphenidate group and 81 (88%) in the placebo group reported using drugs most of the time or always at all visits. Of those who received treatment, 72 (85.8%) in the methylphenidate group and 80 (90.7%) in the placebo group reported that they received the full 20-mg dosage across all visits. Nine study participants (5 in the methylphenidate and 4 in the placebo group) opted to discontinue medication at an intervening study visit but completed follow-up visits.

Baseline Characteristics

Participant demographics and baseline characteristics were similar across treatment groups (Table 1). The median (interquartile range) age of study participants was 76 (71-81) years. Most participants were male (131 [66%]), non-Hispanic (197 [99%]), White (181 [90%]), and had been diagnosed with dementia for about 3 years. Dementia was moderately severe with mean (SD) Mini-Mental State Examination scores of 19.2 (5) in the methylphenidate group and 18.5 (5) in the placebo group. The majority (157 [79%]) of study participants were being treated with dementia medications, including cholinesterase inhibitors (145 [73%]) and/or memantine (76 [38%]). Mean (SD) scores for the apathy subscale of the NPI were 8.0 (2.5) and 7.6 (2.3) in the methylphenidate and placebo groups, respectively, and 1.9 (0.5) on the Dementia Apathy Interview and Rating scale for both groups. A total of 71 participants (36%) were taking selective serotonin reuptake inhibitors at baseline.

Table 1. Baseline Characteristics of Participants.

Characteristic	No./total No. (%)
Characteristic	Total (N = 200)^a	Methylphenidate group (n = 99)	Placebo group (n = 101)
Age, median (IQR), y	76 (71-81)	77 (71-81)	76 (70-81)
Women	68/199 (34)	33/98 (34)	35/101 (35)
Men	131/199 (66)	65/98 (66)	66/101 (65)
Race and ethnicity
Black/African American	12/199 (6)	6/98 (6)	6/101 (6)
Hispanic/Latino	1/199 (0.50)	0/98 (0)	1/101 (1)
White	181/199 (90)	90/98 (92)	91/101 (90)
Other^b	5/199 (2.5)	1/98 (1)	4/101 (4)
Unknown or not reported	1/199 (0.5)	1/98 (1)	0
Marital status
Married	171/199 (86)	83/98 (85)	88/101 (87)
Single	28/199 (14)	15/98 (15)	13/101 (13)
Education
<High school	10/199 (5)	4/98 (4)	6/101 (6)
High school diploma or GED	39/199 (20)	20/98 (20)	19/101 (19)
Some college or associate degree	40/199 (20)	17/98 (17)	23/101 (23)
College degree	58/199 (29)	30/98 (31)	28/101 (28)
Postgraduate degree	52/199 (26)	27/98 (28)	25/101 (25)
BMI, mean (SD)
Women	25.9 (4.5)	25.5 (5.1)	26.3 (3.9)
Men	27.6 (4.3)	27.0 (4.2)	28.2 (4.4)
Age at onset of AD, median (IQR), y	73 (67-78)	73 (67-77)	72 (67-79)
Missing	18/199 (9.0)	13/98 (13.3)	5/101 (5)
Personal psychiatric history before onset of AD
Other dementia	8/199 (4)	4/98 (4)	4/101 (4)
Other mood disorder	6/199 (3)	2/98 (2)	4/101 (4)
No psychiatric disorder reported	143/199 (72)	71/98 (72)	72/101 (71)
Hypertension	117/199 (59)	55/98 (56)	62/101 (61)
Diabetes	31/199 (16)	10/98 (10)	21/101 (21)
Blood pressure level, median (IQR), mm Hg
Systolic	134 (125-149)	132 (124-148)	136.0 (126-150)
Diastolic	77 (70-82)	76 (70-82)	77 (70-82)
Abnormal ECG results
Not clinically significant	118/199 (65)	61/98 (67)	57/101 (63)
Clinically significant	2/199 (1)	1/98 (1)	1/101 (1)
Cigarette smoking behavior
Never	111/199(56)	57/98 (58)	54/101 (54)
Ever	82/199 (41)	38/98 (39)	44/101 (44)
Current	5/199 (3)	2/98 (2)	3/101 (3)
Current medications
Memantine	75/199 (38)	38/98 (39)	37/101 (37)
Cholinesterase inhibitor	145/199 (73)	75/98 (76)	70/101 (69)
Other AD medication	3/199 (1.5)	1/98 (1)	2/101 (2)
Not using any AD medication	42/199 (21)	19/98 (19)	23/101 (23)
Selective serotonin reuptake inhibitor	71/199 (36)	32/98 (32)	39/101 (39)
Serotonin-norepinephrine reuptake inhibitor	13/199 (7)	7/98 (7)	6/101 (6)
Neuropsychiatric Inventory score, mean (SD)
Total	16.4 (9.8)	15.2 (7.5)	17.6 (11.5)
Apathy subscale	7.8 (2.4)	8.0 (2.5)	7.6 (2.3)
DAIR score, mean (SD)	1.9 (0.5)	1.9 (0.5)	1.9 (0.5)
MMSE score, mean (SD)	18.8 (5)	19.2 (5)	18.5 (5)

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Abbreviations: AD, Alzheimer disease; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DAIR, Dementia Apathy Interview and Rating; ECG, electrocardiogram; IQR, interquartile range; MMSE, Mini-Mental State Examination.

^{^a}

Baseline data are missing for 1 participant.

^{^b}

Other included American Indian, Asian, Black, Native Hawaiian, White, and other race.

Hypertension was prevalent across both groups at 56% (55 of 98) and 61% (62 of 101) in the methylphenidate and placebo groups, respectively. The proportion of participants reporting a history of diabetes was lower in the methylphenidate compared with the placebo group (10 of 98 [10%] vs 21 of 101 [21%]).

Apathy Outcomes

At 6 months, using an adjusted longitudinal model, we observed a significant difference between treatment groups in change in the NPI apathy score from baseline to 6 months with a larger difference in the methylphenidate compared with the placebo group (mean difference = −1.25; 95% CI, −2.03 to −0.47; P = .002), equivalent to Cohen d of 0.365 (Table 2; eTable 1 in Supplement 2).

Table 2. Measures of Apathy at 6 Months in Persons With Alzheimer Disease Participating in the ADMET 2 Trial.

Characteristic	No. (%)
Characteristic	Methylphenidate group	Placebo group
No. of participants with data at 6 mo	89	91
NPI apathy subscale
Score at 6 mo, mean (SD)	3.5 (3.4)	4.6 (3.3)
Change from baseline to 6 mo, mean (SD)	−4.5 (4.1)	−3.1 (3.6)
Estimated treatment effect (methylphenidate – placebo), mean (95% CI)^a^,^b	−1.25 (−2.03 to −0.47)
P value	.002
Cohen d	0.365
ADCS-CGIC change in apathy at 6 mo
Improvement
Marked	2 (2.2)	2 (2.2)
Moderate	14 (15.7)	10 (11.0)
Minimal	23 (25.8)	20 (22.0)
No change	42 (47.2)	40 (44.0)
Worsening
Minimal	7 (7.9)	16 (17.6)
Moderate	1 (1.1)	3 (3.3.)
Marked	0 (.00)	0 (0.0)
Estimated treatment effect (methylphenidate vs placebo), OR (95% CI)^b	1.90 (0.95-3.84)
P value	.07
Estimated difference in mean change from baseline to 6 mo (methylphenidate vs placebo), OR (95% CI)^c	1.43 (1.00-2.04)
P value	.048

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Abbreviations: ADCS-CGIC, Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change; ADMET, Apathy in Dementia Methylphenidate Trial; NPI, Neuropsychiatric Inventory; OR, odds ratio.

^{^a}

Estimated in a longitudinal model for mean difference between arms in change from baseline, using a linear mixed model with random intercept for each participant, adjusting for clinic, age, sex, and diabetes condition.

^{^b}

Estimated difference in proportional odds of improvement at 6 months.

^{^c}

Estimated in a longitudinal model for mean difference between arms in change from baseline, for all follow-up visits, adjusted for clinic, participant sex, and diabetes condition.

The largest change in NPI apathy occurred during the first 2 months of treatment (Figure 2). At month 6, 27% (24 of 89) of participants in the methylphenidate group had an NPI apathy score of 0 compared with 14% (13 of 90) in the placebo group. We estimated the rate at which participants achieved an NPI apathy score of 0, using Kaplan-Meier curves and observed a hazard ratio of 1.57 (95% CI, 0.97-2.53; P = .07) over the entire follow-up period (Figure 3). We observed a significant difference in the hazard ratio change (2.16; 95% CI, 1.19-3.91; P = .01) for the first 100 days, suggesting that the methylphenidate group demonstrated a decrease in the NPI apathy subscale sooner than the placebo group during this initial time period.

Figure 3. — Censored events are noted by X’s. Over the complete follow-up period of 6 months, the methylphenidate group had a 57% increase in the hazard ratio compared with the placebo group (hazard ratio, 1.57; 95% CI, 0.97-2.53; P = .07). For the first 100 days of follow-up, the methylphenidate group had more than twice the increase in the hazard ratio compared with the placebo group (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). The model was adjusted for age, sex, and presence of diabetes.

At 6 months, 43.8% (39 of 89) of participants in the methylphenidate group showed improvement compared with 35.2% (32 of 91) of study participants in the placebo group in the ADCS-CGIC (Table 2). The odds ratio of having an improved rating on the ADCS-CGIC for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07), favoring methylphenidate over placebo. Using an adjusted longitudinal model, the odds ratio for difference in mean change from baseline to 6 months between treatment groups was 1.43 (95% CI, 1.00-2.04; P = .048). It should be noted that there was a strong association between improvement in NPI apathy and ADCS-CGIC apathy subscales (odds ratio, 2.95; 95% CI, 1.48-5.97; P = .002) and between improvement in NPI apathy subscale and overall ADCS-CGIC (odds ratio, 6.10; 95% CI, 1.35-56.67; P = .009) (eTables 2 and 3 in Supplement 2). Both groups showed a decrease in apathy from baseline to 6 months on the Dementia Apathy Interview and Rating (mean [SD]; −0.5 [0.8] in the methylphenidate and −0.4 [0.7] in the placebo group).

There were no significant treatment interactions by sex or race other than White. The results were similar for all other sensitivity analyses (data not shown).

Other Neuropsychiatric Symptoms

We observed no change in other neuropsychiatric symptoms, except for increased NPI aberrant motor behavior in the methylphenidate compared with the placebo group (mean difference 0.69; 95% CI, 0.09-1.25; P = .03) (eTable 4 and eFigures 1 and 2 in Supplement 2).

Adverse Events

There were 17 serious adverse events in the methylphenidate group and 10 in the placebo group (eTable 5 in Supplement 2), all hospitalizations for nonrelated events. More participants in the methylphenidate group lost more than 7% of their baseline body weight at follow-up (10 vs 6, respectively). Of these, 4 in each group had a body mass index (calculated as weight in kilograms divided by height in meters squared) greater than 25 at baseline. Other adverse events showed no important differences (eTable 6 in Supplement 2).

Cognitive and Other Measures

We found no treatment difference in cognitive measures (eTable 7 in Supplement 2), Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale, Dependence Scale, or EuroQol (eTable 8 in Supplement 2). Resource utilization data will be presented in a subsequent article.

Discussion

In this study, methylphenidate treatment was associated with a small to medium reduction in apathy in patients with AD as shown by the NPI apathy subscale. These findings were first observed 2 months after treatment initiation and sustained over 6 months. The ADCS-CGIC did not show a statistically significant difference, but there was a trend favoring methylphenidate (eTable 9 in Supplement 2). Measures of caregiver distress did not show a statistically significant difference. However, both improvement in ADCS-CGIC and in measures of caregiver distress (eFigure 3 in Supplement 2) were associated with improvement in apathy, suggesting the clinical relevance of improvement in apathy as shown in this study. Adverse events were generally modest and consistent with those expected with methylphenidate.

The development of this study was based on data suggesting that the use of catecholamine/dopamine-enhancing agents is a promising and feasible approach to treat apathy in AD. This approach is based on the understanding that motivated behavior relies on subregions of the prefrontal cortex (dorsolateral, orbital-ventromedial, dorsomedial), which degenerate in AD resulting in apathetic behaviors. Methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.¹⁵ Studies evaluating potential treatments for apathy in AD are limited and the results of some of them have been disappointing.^38,39,40 However, 2 small trials evaluating the treatment of apathy in AD with methylphenidate have shown evidence of safety and efficacy in treating apathy.^17,18,19 ADMET 2 was designed to examine the efficacy and safety of methylphenidate as treatment for clinically significant apathy in participants with AD, where efficacy was measured by looking at changes in apathy and cognition. ADMET 2 results are similar to prior studies showing a small to medium efficacy of methylphenidate as soon as 2 months after initiating treatment. Additionally, it is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition.

Patients experiencing major depressive episode as diagnosed by the Diagnostic and Statistical Manual of Mental Disorders may experience some of the same symptoms as those experiencing apathy, those are 2 very distinct clinical entities. Apathy is characterized by a lack of affect, while depression is characterized by an overwhelming presence of a negative affect and mood. Furthermore, literature has shown the lack of response of symptoms of apathy to selective serotonin reuptake inhibitors, supporting the importance of the distinction and providing evidence of 2 very different biological pathways.^41,42 Most individuals in the study were also receiving currently approved AD treatments. The effect of concomitant medication, including cholinesterase inhibitors, memantine, and/or antidepressants, was examined, and we did not observe any effect in study results. Furthermore, doing so reflects clinical practice, where apathy would remain after stabilization on cognitive enhancers.

Limitations

Limitations of the study include the following: (1) participants composed a convenience sample of mainly White individuals in US and Canadian academic medical centers that may not generalize to other settings or to non-AD forms of dementia; (2) we did not obtain biomarker confirmation for the diagnosis of AD; (3) treatment was limited to 6 months; and (4) lack of data on potential participants who declined to participate or failed screening.

Conclusions

Apathy is a prevalent and clinically significant neuropsychiatric symptom in AD. Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers. The efficacy has a relatively early onset and its effect is sustainable for at least 6 months. Clinicians should be aware of the small to medium treatment effects sizes and the lack of effect on activities of daily living.

Supplement 1.

Trial Protocol

Click here for additional data file.^{(601.4KB, pdf)}

Supplement 2.

eTable 1. Apathy/indifference from the Neuropsychiatric Inventory (NPI) by visit and treatment assignment

eTable 2. CGIC apathy (any vs no improvement) by change in NPI apathy score from baseline, categorized at median change at F6

eTable 3. Overall CGIC (any vs no improvement) by change in NPI apathy score from baseline, categorized at median change at F6

eTable 4. Average change in NPI neuropsychiatric symptom by treatment assignment and difference in change between treatment assignment at F6, observed and modelled

eTable 5. Participants reporting serious adverse events during follow-up by treatment assignment

eTable 6. Participants reporting non-serious adverse events during follow-up by treatment assignment

eTable 7. Change in cognitive score at 6 months by treatment group

eTable 8. EuroQol scores at baseline and 6 months follow-up by treatment group

eTable 9. Average change in apathy based on Alzheimer’s Disease Cooperative Study (ADCS) - Clinical Global Impression of Change (CGIC) classification by treatment assignment and difference in change between treatment assignment at F6, observed and modelled, and by visit

eFigure 1. Proportion of participants with neuropsychiatric symptoms other than apathy from the Neuropsychiatric Inventory (NPI) by visit and treatment assignment

eFigure 2. Severity of neuropsychiatric symptoms other than apathy from the Neuropsychiatric Inventory (NPI) by visit and treatment assignment

eFigure 3. Proportion of caregiver distress by visit and treatment assignment

Click here for additional data file.^{(563.5KB, pdf)}

Supplement 3.

Nonauthor Collaborators. The ADMET 2 Research Group

Click here for additional data file.^{(114.2KB, pdf)}

Supplement 4.

Data Sharing Statement

Click here for additional data file.^{(15.5KB, pdf)}

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