Heterogeneity of response to methylphenidate in apathetic patients in the ADMET 2 Trial
Bibliographic record
Abstract
Abstract Background 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. Method 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. Result 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. Conclusion 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.026 | 0.022 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.007 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".