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. We assessed response in ADMET 2 to identify individuals likely to benefit from methylphenidate.

In ADMET 2, AD patients with clinically significant apathy were randomized to methylphenidate or placebo. Twenty-three potential predictors of treatment outcome chosen a priori for evaluation were divided into levels (e.g. anxiety present/absent). For each predictor, change in Neuropsychiatric Inventory apathy (NPI-A) due to methylphenidate for each level was estimated. Predictors with larger differences in effect (>= 2pt NPI-A) between levels were selected. Participants were then grouped into 10 subgroups by their index scores, constructed based on model-based prediction of response (NPI-A >=4).

In total 177 participants (66% male, mean (SD) age 75.7 (8.0), Mini-Mental State Examination 18.9 (4.8)) had 3 month follow-up data. Six potential predictors met criteria for multivariate modelling. The median Index score was -1.33 (range: -8.35 to 6.83). Methylphenidate was more efficacious in participants with no NPI anxiety (change in NPI-A - 2.21, Standard Error (SE):0.60, p=0.0004) or agitation (-2.63, SE: 0.68, p=0.0002), and who were on cholinesterase inhibitors (ChEI) (-2.44, SE:0.62, p=0.0001), between 52-72 years of age (- 2.93, SE:1.05, p=0.007), had normal diastolic blood pressure (-2.43, SE: 1.03, p=0.02), and more functional impairment (-2.56, SE: 1.16, p=0.03) as measured by the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale. After 3 months of methylphenidate, 79% of participants with a higher index score (>median) responded (>= 4pt NPI-A) and 49% of those with a lower index score responded.

Individuals who were less anxious or agitated, younger, on a ChEI, had normal diastolic blood pressure, and with more impaired function were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for apathetic AD participants with lower baseline anxiety and agitation.