Partial Tolerance to Methylphenidate in ADHD?

Little is known about long-term outcome of persons diagnosed with and treated for attention deficit/hyperactivity disorder (ADHD) in childhood or adolescence.

That approximately half of the children and adolescents who begin stimulant pharmacotherapy are no longer receiving it ten years later broaches a possibility that ADHD may represent a self-limited anomaly of neurodevelopment—a normal variant that some youth “out-grow.” Others have documented associations between having been diagnosed with ADHD in childhood and increased rates of substance use disorders, marital problems, and occupational instability in adulthood.

Whether adult manifestation of childhood-onset disorder or adult-emergent depredation of ADHD-related dysfunctional maturation during youth, the core symptoms defining what we now call ADHD and the behavioral features of its adult-emergent sequelae improve and are reported to be preventable, respectively, by central nervous system stimulants (amphetamines, methylphenidate, and modafinil—phenylethylamine congeners that trigger bursts of electrochemical activity in prefrontal cortex by dint of releasing newly synthesized dopamine from presynaptic axon terminals, raising synaptic dopamine concentrations, and thereby increasing the likelihood of interaction with dendritic dopamine receptors to initiate chemical signals that affect still obscure processes that give rise to the clinical effects of stimulants).

Stimulant response rates are high, as are effect-sizes in mitigating inattentiveness and hyperactivity.  Effects are persistent, in that they appear no less robust when stimulants are maintained for long durations (long enough to “fine tune” dosage to optimal), and yet a preponderance of stimulant effects—including psychomotor stimulation—are subject to tolerance development with the same daily dosing that comprises treatment for ADHD (a distinct boon, relative to adverse effects, such as sleep disturbance, anorexia, and elevations of heart rate and blood pressure), suggesting that therapeutic effects of stimulants in ADHD may differ from cognitive enhancements documented in normal subjects and regarded as features that define stimulant activity (such as enhanced alertness, attention span, working memory, some types of short-term memory, faster reaction times and lower error rates on some psychomotor performance tests).

Contrariwise, therapeutic effects of stimulants on inattentiveness and hyperactivity in ADHD may represent the same cognitive and psychomotor enhancement in persons with ADHD, and would persist if the tolerance that develops to conventional stimulant effects were incomplete.

Yet a third rendering of existing literature on stimulant effects in persons with and without ADHD is possible, and may obtain with best fit: To wit, that stimulant effects may differ between persons with and without ADHD in the respect of tolerance itself, which may represent the same processes in both, but manifest as residual therapeutic effect in the more cognitively impaired population.

Doubtless, much that may clarify effects of stimulants on persons with ADHD and on normal subjects depends upon how much tolerance develops to stimulants with respect to their effects on ADHD, and a recently reported study by Netherlands researchers Anne-Flore Matthijssen and colleagues (American Journal of Psychiatry, published online on May 21, 2019), of the University of Groningen, is intended to illuminate that very question.

Using a placebo-controlled, methylphenidate-withdrawal protocol, the authors first administered methylphenidate or placebo to 94 children and adolescents (8-to 18-years-old) who previously had been treated with methylphenidate over at least two years (range = 2 to 8.5 years) (response unspecified).

After baseline assessment (using investigator-administered ADHD-RS (inattention and hyperactivity) scales; Clinical Global Impressions Improvement ratings, and (in those for whose parents gave consent) Conners Teacher Rating Scale scores)), the authors switched 47 (randomly allocated) patients with ADHD from previous methylphenidate formulations to the osmotically-released formulation of methylphenidate (generic Concerta, 36 or 54 milligrams per day) for seven weeks. The other (randomly selected) 47 patients with ADHD were tapered from methylphenidate over four weeks, whereafter they received placebo for three consecutive weeks. At the end of seven weeks, the authors assessed their patients as they had at baseline and at end-of-study times for those who failed to complete seven weeks.

As expected, total and (both) subscale ADHD-RS rating scores were similar between groups at baseline. Over the seven weeks of study, investigator-administered ADHD-RS ratings and one of the two subscales (that for inattention) showed statistically significant differences of small effect size that favored the methylphenidate-treated patients. Among patients receiving methylphenidate during the last three weeks of study, the statistical significance of the difference in ADHD-RS inattention subscale ratings was attributable to change in a subgroup of young patients—no change in ADHD-RS total or subscale ratings was observed in children with a mean age of 13.8 or older). Changes in the hyperactivity subscale were similar for patients continuously dosed with, and patients withdrawn from, methylphenidate during the last three weeks of the authors’ seven-week study.

Also distinguishing the two groups were Clinical Global Impressions Scale ratings, as percentage of each group considered to have “worsened” by the end of study: 40.4 percent of the patients in whom methylphenidate had been discontinued and 15.9 percent of the patients in whom it had not been. Consistently, Conners Teacher ratings indicated worsening of hyperactivity (but not of inattentiveness) only in patients who had been withdrawn from methylphenidate.

The authors believe that children and adolescents with ADHD continue to benefit from methylphenidate after two to almost nine years of continuous treatment. Though they acknowledge tolerance development apropos of other methylphenidate effects, they conclude that it does not occur with respect to the (still obscure) processes affected by methylphenidate in ADHD. (Obiter: Yet, the authors’ very findings suggest incomplete tolerance to the therapeutic benefit of methylphenidate: their subjects differed on investigator ratings with respect to inattention, but not hyperactivity, and the former was attributable to changes in a younger stratum of subjects (whose duration since diagnosis and duration of treatment presumably had been briefer than those of the older patients with ADHD.  While the global ratings differed with respect to the proportion of patients with “worsening” after methylphenidate discontinuation was larger, no other dimension of the global ratings differed (that is, “slightly, much,” or “very much worse” were not all individually different and required collectivization). Moreover, Conners teacher ratings showed no difference between groups in items pertaining to inattentiveness. If the patients all had been receiving optimal methylphenidate dosages before tapering and discontinuation of methylphenidate, “partial worsening” after methylphenidate discontinuation may indicate incomplete tolerance to methylphenidate before.)

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