Letter: Paradoxical Sedation on Methylphenidate in a Child with Attention-Deficit/Hyperactivity Disorder

To the Editor:

An 8-year-old Syrian boy was referred by the school counselor to our outpatient clinic for repeated disruptive behavior with subsequent disciplinary measures and subpar scholastic achievement. He had normal developmental milestones and a history of atopic dermatitis. He kept only little company that could withstand his reported moodiness, though no comorbid bona fide mood disorders could be elicited in history or mental status examination. He had no genetic load of psychiatric illnesses, nor did he have a history of head trauma, epilepsy, tics, abuse, or toxic exposures. Baseline workup including thyroid function tests were within normal as were iron studies. Vitamin D was deficient and he was on replacement therapy. Electroencephalography was conducted, for a past history of febrile seizures at age of 4 years, and was normal. Psychometry using Vanderbilt Assessment Scales for attention-deficit/hyperactivity disorder (ADHD) were completed, both Parents and Teacher Versions, and confirmed ADHD-hyperactive/impulsive (H/I) presentation, severe (8/9 for hyperactive/impulsive subscale). Full Scale Intelligence Quotient measured using Wechsler Intelligence Scale for children-Third Edition read 84, with no scatter. There was no known drug allergy, and apart from vitamin D, no other medications were prescribed. He was commenced on methylphenidate-immediate release (MPH-IR) 5 mg thrice a day (tds) (weight of 31 kg). On day 1, almost an hour after first dose (MPH 5 mg), parents noted the child was sleepy, oversedated, and lethargic. They were reluctant to continue with subsequent doses and escorted him to our urgent care, where he was thoroughly assessed, medically cleared with blood chemistries and Electrocardiogram performed but unrevealing. As MPH wears off (3–4 hours), child was back to normal. Parents were reassured and MPH was resumed but at a lower dose of 2.5 mg tds. Once again, the child had the same reaction to the first morning dose and the parents declined to continue the trial. We opted to swap to mixed amphetamine salts or atomoxetine. One of the authors (A.N.) suggested increasing dose of MPH instead and rechallenging. To our surprise, when trialed on MPH 10 mg, the child responded favorably with no tolerability issues or oversedation compared withthe 2.5 and 5 mg doses. We continued with MPH 10 mg tds/day and over a couple of weeks, tangible gains spanning behavioral, academic and social domains were noted by parents and corroborated with positive school reports. This was achieved with great tolerability. Three months elapsed at the time of writing this report, and the response is well maintained.

We could locate two relevant cases. One, a 6-year-old boy, known case of autism spectrum disorder/ADHD, developed lethargy and sleepiness on mixed amphetamine salts (Al Awami & Albanna, 2020). The other one, a 6-year-old boy, known case of ADHD/oppositional defiant disorder, developed oversedation on lisdexamfetamine dimesylate (Majeed et al, 2019). In both cases, changing medications was helpful. No attempt to increase dose (as in our report) was pursued.

Furthermore, paradoxical sedation was once thought of as a contributory mode of action of stimulants for ADHD, but this has largely been debunked.

Increasing the dose of psychostimulants in these cases might sound counterintuitive as sedation might be expected to increase accordingly. We do believe, though, that is not the case with stimulants, because this is a paradoxical reaction. We assume, increasing, rather than decreasing the dose, would boost further dopamine/nor-adrenaline (NA) tone in the prefrontal cortex accounting for more vigilance and alertness. Although genotyping for a possible slow metabolizer status could have been informative in this particular case, the alerting response on the higher dose would retrospectively defy this notion.

This type of pharmacological reaction has been similarly demonstrated for benzodiazepines (BDZs’) paradoxical excitement—where increasing, instead of decreasing, BDZ dose, can help with disinhibition (Turkoglu, 2015). Also, this is seen for antipsychotic-related tardive dyskinesia (TD), where increasing dose of antipsychotic initially can suppress TD. Likewise, with mirtazapine, sedation is typically mitigated with further dose increments, where NA drive would override antihistaminergic actions (Naguy et al, 2023).

It behoves clinicians to be mindful of these rare paradoxical reactions to psychostimulants and to try to increase the dose before dropping the trial altogether.