Contents

1 Variability of Response to MPH treatment

There is a large intersubject variability for methylphenidate (MPH) induced increases in extracellular dopamine (DA) and dopamine transporter (DAT) blockade with a fixed dose of MPH [12]. Some small children require high doses and some large children require small doses, so adjustment for weight does not account for this range [9]. Neither do differences in absorption and metabolism [9], since children who respond to low doses (5 mg per administration) have low serum concentrations of MPH (4 ng/mL to 5 ng/mL at T_max) and those who respond to high doses (20 mg per administration) have high serum concentrations (12 ng/mL to 15 ng/mL).

2 MPH effect on DA levels

A relatively large therapeutic dose of oral MPH (60 mg) significantly blocked DATs in all subjects (measured using positron emission tomography (PET)) but did not increase extracellular DA in all of them [12]. Volkow et al. [12] suggests that individual differences in MPH-induced increases to DA may reflect differences in DA tone between subjects. Since the pharmacological responses to MPH will also depend on the sensitivity of DA regulated circuits, differences in sensitivity of these circuits to DA stimulation is also likely to contribute to the large intersubject variability in MPH’s effects [12]. This is consistent with the findings that homovanillic acid (HVA) levels in cerebrospinal fluid (CSF) (a marker of DA turnover in the central nervous system (CNS)) predicts response to MPH in children with ADHD: the higher the levels, the better the responses [3]. It also suggests a plausible mechanism that may underlie nonresponse to MPH, which occurs in 15 % to 30 % of children with attention-deficit/hyperactivity disorder (ADHD) [9], or the requirement for very high doses to produce clinical effects, which is required in about 20 % of those who are considered responsive to stimulants.

MPH-induced increases in DA declined as a function of age [10]. This could reflect the decrease in DAT that occurs with age. In fact, one could speculate that the age-associated decline in DAT could contribute to the decrease in symptomatology in most of the ADHD subjects as they grow older [2]. Alternatively the fact that the elevations of DAT in ADHD subjects were reported in adults [4] suggests that a failure to show DAT decline with age could account for the persistence of symptomatology in subjects with ADHD. This could also explain the therapeutic efficacy of MPH in adults with ADHD [8].

3 Effects of increased Dopamine

DA cells fire in response to salient events, which is a mechanism by which the brain signals that a stimulus is relevant and should be attended to, and indeed, increases in DA induced by MPH were linked to an enhanced perception of events as salient [14]. In Volkow et al. [11], the study evaluated the effects of MPH on appetitive stimuli using PET and [¹¹C]raclopride to compare the changes in DA induced by food stimuli (visual and olfactory presentation of food in food-deprived individuals) versus neutral stimuli (description of family genealogy) when given with placebo or with MPH (20 mg oral) and in parallel evaluated the self-reports for the ‘desire for the food’ and for ‘hunger’ [11]. This study showed that MPH induced significant increases in DA in dorsal striatum when given with food stimuli but not when given with the neutral stimuli. In contrast, no differences in DA were found among placebo-treated subjects exposed to food stimuli, suggesting that stimulus presentation alone was not strong enough to induce a DA change large enough to be detected by PET. MPH also increased the ratings in self-reports for ‘desire for food’ and for ‘hunger’ when exposed to the food stimuli as compared with placebo. The increases in the perception of hunger and desire for food were correlated with MPH-induced increases in extracellular DA in dorsal striatum. These findings support the role of MPH in enhancing DA signal saliency for appetitive stimuli [14].

MPH also increased extracellular DA in the striatum when administered before subjects were required to perform a remunerated mathematical task, but not when MPH was administered before subjects passively viewed scenery cards [13]. MPH increases the ratings of cognitive tasks as being interesting, exciting, motivating, and less tiresome [7, 13]. This suggests that MPH amplifies small DA increases due to the task, and this may be the mechanism underlying this drug’s ability to make tasks more salient to the subject [13]. MPH’s therapeutic attentional effects may be secondary to its ability to enhance stimuli-induced DA increases, thus making them more motivationally salient and thereby improving performance [7, 13], which would explain why stimulants improve performance of a boring task in normal healthy individuals and why unmedicated ADHD children perform properly when the task is sufficiently salient to them [1, 5, 6].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

CNS

central nervous system

CSF

cerebrospinal fluid

DAT

dopamine transporter

DA

dopamine

HVA

homovanillic acid

MPH

methylphenidate

PET

positron emission tomography

References