Advances in the Pharmacotherapy of Attention‐Deficit‐Hyperactivity Disorder: Focus on Methylphenidate Formulations

Abstract

The psychostimulant dl-methylphenidate (MPH) remains the most common drug therapy in child and adolescent psychiatry for the treatment of attention-deficit-hyperactivity disorder (ADHD). Evidence of a dopaminergic basis both for the actions of MPH and for the underlying neuropathology in ADHD continues to mount. Advances in the biopharmaceutics of MPH have been conspicuous. Novel approaches to formulation design have resulted in new MPH delivery options to overcome the short-term actions of both immediate-and sustained-release MPH. New modified-release MPH products offer the convenience of once-daily administration while providing extended absorption profiles that better mimic those of standard schedules of immediate-release MPH (i.e., the absorption phase of MPH better correlates with improved behavioral response than does the elimination phase). The oral bioavailability of MPH in females may be lower than in males. The l-MPH isomer exhibits only negligible oral bioavailability and, further, possesses little intrinsic activity at the dopamine transporter. This notwithstanding, a single-isomer d-MPH immediate-release product is now available for dosing recommended at one-half that of dl-MPH.

A Review of Pharmacological Management of Attention-Deficit/Hyperactivity Disorder

“…Methylphenidate exerts its action on both dopamine and norepinephrine transporters, thus it is believed to increase dopamine and norepinephrine in the prefrontal cortex. 16 There are various formulations available. The immediate-release formulations are usually started for younger and smaller children (i.e., <16 kg) who are naïve to psychostimulants.…”

“…Food does not change the overall benefit of methylphenidate administration; however, with the long-acting, solid dosage formulations, a high-fat meal eaten at the same time of administration may delay the onset of action. 16 Titration to maximum effective dose can occur quite quickly, since the clinical benefit can be seen within a few days to 1 week. Thus, clinicians can titrate doses every 7 days.…”

“…If a child or adolescent only needs help during school, the product chosen should provide about 6 to 8 hours of action, whereas if a child or adolescent needs benefit to maintain after-school activities, including homework and driving, a 12-hour product should be considered. 16,27 The usual initial regimen starts with an immediate-release psychostimulant administered twice daily (e.g., 5 mg two times daily) for those that are smaller in weight (i.e., <16 kg), 1 and then the dose is titrated to a maximum effective dose producing minimal side effects. In children who are older and larger, and adolescents, the smallest effective dose should be initiated and titrated upwards.…”

Enantiospecific gas chromatographic–mass spectrometric analysis of urinary methylphenidate: Implications for phenotyping

“…1). Optimization of pharmacotherapy in ADHD generally requires some empiricism and approximately 20-30% of ADHD patients do not respond favorably to dl-MPH at any dose [2]. New medications for ADHD continue to be developed and include enantiopure d-MPH [3].…”

A novel HPLC fluorescence method for the quantification of methylphenidate in human plasma

“…The psychostimulant dl-methylphenidate (MPH) is the most frequently employed medication in the pharmacotherapy of attention-deficit hyperactivity disorder (ADHD), the most common neurobehavioral disorder diagnosed among children [1,2]. The marked individual variability in the dose-response relationship of MPH has been well documented over nearly 50 years of clinical use.…”