Therapeutic Doses of Methylphenidate
Contents
1.1 Experiments in mice
2 Selective metabolism of MPH isomers
3 Variability of Response to MPH treatment
3.1 Response Variability based on Impulsivity
3.2 Non-responders
1 Therapeutic Doses of Methylphenidate
Though methylphenidate (MPH) is very effective for the treatment of attention-deficit/hyperactivity disorder (ADHD) the doses required to achieve clinical responses vary significantly across individuals (0.1 mg/kg to 1 mg/kg) [18]. Similarly the responses to MPH when given in a laboratory setting for research purposes are also quite variable. Other than differences in metabolism of MPH, part of the variability in the behavioral responses to MPH are due to differences in dopamine (DA) cell activity and in the levels of DA D2 receptors between subjects [20, 21].
For a typical 25 kg child the maximum serum concentration is expected to be about [17]: 5 ng/ml for a low dose (5 mg; 0.2 mg/kg), 10 ng/ml for a medium dose (10 mg; 0.4 mg/kg), and 20 ng/ml for a high dose (20 mg; 0.8 mg/kg). Regardless of dose, time to maximum (Tmax) is expected to be about 1.5 h to 2 h [17], and half-life (T1∕2) is expected to be 2 h to 3 h [17]. The maximum behavioral effects (reduction in overactivity, impulsivity, and inattention) occur about 1 h to 2 h after oral doses [17], behavioral effects dissipate significantly by 2 h after max behavioral effect (3 h to 4 h after each dose) [17]. Oral MPH at doses used therapeutically induce greater than 50 % dopamine transporter (DAT) blockade with an estimated median effective dose (ED50) dose of 0.25 mg/kg
1.1 Experiments in mice
Oral dose of 0.75 mg/kg MPH can produce plasma levels of d-MPH in the 6 ng/ml to 10 ng/ml range in mice [2]. 2 ng/ml to 9 ng/ml represents the lower limit of the clinical range, whereas a 3 mg/kg dose was predicted to produce peak plasma concentrations between 30 ng/ml to 60 ng/ml, corresponding to upper limits of the clinical range [7]. Brain concentrations were 4- and 5-fold higher than the plasma concentration going up to 6–8 fold higher than plasma at 30 min with a low dose of MPH [2]. Higher doses had less brain loading by proportion, with a brain/plasma ratio below 1 at 2 mg/kg to 5 mg/kg dose for early time periods, and increasing once plasma levels drop [2].
2 Selective metabolism of MPH isomers
Therapeutic effects of oral dl-MPH appear to be limited to the d-MPH isomer [1, 4, 9, 16], as consistent with a pure d-MPH formulation (dexmethylphenidate; Focalin®;) becoming available in 2002. Any potential benefit of removing the l-MPH isomer from an oral dl-MPH formulation is not obvious [15], due to the very extensive oral pre-systemic metabolism of l-MPH: typically only low pg/mL concentrations of the l-isomer reach the systemic circulation [4, 10, 12, 22]. This trace l-MPH plasma concentration represents only about 1 % of the d-MPH plasma concentration [13]. In effect, oral dl-MPH in humans is subject to in vivo biocatalytic resolution by carboxylesterase 1 [23], analogous to the enzymatic approach that has been used industrially to eliminate l-MPH from dl-MPH and yield enantiopure d-MPH [13].
3 Variability of Response to MPH treatment
Imaging studies have documented large variability in the magnitude of the changes in extracellular DA induced by MPH. After oral administration of 60 mg MPH the range of changes in extracellular DA was 3 % to 48 % [20]. While this variability is in part related to age, a large percentage of the variability still remains unaccounted by age. The levels of DAT blockade in these subjects did not predict the changes in extracellular DA as assessed by decreases in DA D2 receptor availability. Volkow et al. [19] suggest this lack of a correlation as an indication that the DA increases were due not just to DAT blockade by MPH but to the individual variability in the amount of DA released by the DA cells. This is consistent with the findings that homovanillic acid (HVA) levels in cerebrospinal fluid, which serve as a marker of DA turnover in the central nervous system, predicted response to MPH in children with ADHD; the higher the levels the better the responses [3].
3.1 Response Variability based on Impulsivity
MPH treatment reverses attentional impairments induced with NMDA glutamate antagonist, muscarinic acetylcholine receptor (mAChR) antagonist, nicotinic acetylcholine receptor (nAChR) antagonist [14], and also eliminated impairments of attention and memory in the ‘spontaneous hypertensive rat’ model [6]. This is consistent with the suggestion that psychostimulants only improve impulse control under conditions in which baseline levels of impulsivity are high, as is seen in patients with ADHD [11]. Dose-effect functions need to be carefully assessed in testing drug effects on attentional function in animal models because all drugs which improve attention have an inverted U-shaped dose-effect function in which either lower or higher than optimal doses are less effective and even impairing [8]. The combination of this characteristic non-monotonic dose-effect function with the fact that there is often considerable individual variability in drug sensitivity can complicate detection of beneficial responses to attention-improving drugs.
3.2 Non-responders
As yet no explanation has been found for the fact that about one third of children with ADHD do not clinically respond to MPH [5]. ‘Non-responders’ to MPH treatment had higher levels of both d-MPH and l-MPH enantiomers in plasma at all time points taken than ‘responders’, leading them to think that d-MPH may be getting into the brain more in ‘responders’ than in ‘non-responders’, leaving more MPH in blood plasma in ‘non-responders’ [5]. MPH’s effects are dependent on the rate of DA release. This, in turn, provides an explanation for the variability in the responses to MPH: subjects with high DA tone will be more sensitive to MPH’s therapeutic effects than those with a low DA tone [19]. It also provides an explanation for non-responsiveness, which could reflect very low endogenous DA activity.
Acronyms
- ADHD
- attention-deficit/hyperactivity disorder
- DAT
- dopamine transporter
- DA
- dopamine
- ED50
- median effective dose
- HVA
- homovanillic acid
- mAChR
- muscarinic acetylcholine receptor
- MPH
- methylphenidate
- nAChR
- nicotinic acetylcholine receptor
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