Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease

Abstract

OBJECTIVETo measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease. DESIGN, SETTING, AND PARTICIPANTSThis 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 MEASURESThe 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. RESULTSOf 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.

Rosmarinus officinalis and Methylphenidate Exposure Improves Cognition and Depression and Regulates Anxiety-Like Behavior in AlCl3-Induced Mouse Model of Alzheimer’s Disease

“…Based on clinical anecdotal reports, MPH is being considered for the treatment of apathy in AD, and preliminary trials have shown promising outcomes (Padala et al, 2018;Mintzer et al, 2021).…”

Longitudinal decline in striatal dopamine transporter binding in Parkinson’s disease: Associations with apathy and anhedonia

“…Methylphenidate, a noradrenaline-dopamine reuptake inhibitor, has recently been found to have efficacy in treatment of apathy in Alzheimer’s dementia. 52 Further understanding of the effects of dopaminergic medication regime on apathy and anhedonia in PD is needed, in addition to RCTs of dopaminergic agents for apathy and anhedonia across different disorders.…”

New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

“…Drugs known to increase alertness, such as modafinil, amphetamine and cocaine, act by inhibiting reuptake, as do antidepressants such as reboxetine, venlafaxine and duloxetine 67 . Methylphenidate, the mainstay of ADHD treatment, acts by inhibiting both NE and dopamine reuptake in the PFC to improve attention and memory 125 and has been suggested as a potential treatment for attentional impairment and apathy in AD 60 , with a recent placebo‐controlled study showing that it does reduce the latter 126 …”

“…67 Methylphenidate, the mainstay of ADHD treatment, acts by inhibiting both NE and dopamine reuptake in the PFC to improve attention and memory 125 and has been suggested as a potential treatment for attentional impairment and apathy in AD 60 , with a recent placebo-controlled study showing that it does reduce the latter. 126 Atomoxetine is by far the most extensively studied drug of this class. As well as its established benefits in ADHD, atomoxetine has been shown to boost executive function in PD and is both safe and tolerable.…”