Methylphenidate: Why Getting the Right Dose Is Important, and Challenging

Barbara Geller, MD

An animal study shows enhanced learning at lower doses and hyperactive behaviors at higher ones.

In children with attention-deficit/hyperactivity disorder (ADHD), methylphenidate at lower doses is optimal for learning, whereas higher doses improve classroom behavior (Science 1977; 198:1274). Across the age span and in both clinical and healthy populations, methylphenidate can induce agitation and psychosis. To study the pathophysiology of these phenomena, researchers examined behavior and glutamatergic signaling in the prefrontal cortex in adolescent rats injected with low- or high-dose methylphenidate; doses were relevant to those used clinically in humans.

Low doses were associated with improved memory and attention; high doses were associated with worsened memory, inability to complete the attention task, and marked hyperlocomotion. Low dosing was also associated with increased N-methyl-D-aspartate receptor (NMDAR) expression and greater NMDAR-mediated excitatory postsynaptic currents (EPSCs), whereas high dosing was associated with reduced NMDAR and AMPA receptor expression and lower NMDAR- and AMPAR-mediated EPSCs. Adrenergic antagonists abolished the low-dose effects, and noradrenergic agents mimicked them, establishing that low-dose effects were noradrenergic.

Citation(s):

Cheng J et al. Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors. Biol Psychiatry 2014 Apr 8; [e-pub ahead of print].