REVIEW OF: Pan PY and Yeh CB, J Affect Disord 2025;387:119546

STUDY TYPE: Randomized double-blind placebo-controlled pilot trial

Irritability is common in pediatric ADHD, often persists despite stimulant treatment, and predicts worse long-term outcomes, yet targeted treatment options are limited. This small trial explores whether dextromethorphan (an NMDA antagonist with data in pseudobulbar affect and irritability in depression and adult autism) can augment methylphenidate.

Nineteen children ages 7–17 with ADHD and significant irritability were enrolled in this 8-week trial. All received open-label methylphenidate and were randomized to adjunctive dextromethorphan or placebo. Dextromethorphan began at 30 mg/day and increased to 60 mg/day after 2 weeks. The primary outcome was parent-rated irritability (Affective Reactivity Index); secondary outcomes included ADHD symptoms (Connors) and broader behavioral measures (Child Behavior Checklist [CBCL]).

Dextromethorphan produced marked reductions in irritability (Hedges’ g: 1.88 at week 2, 1.78 at week 4, 0.9 at week 8), which remained significantly lower at week 8, though the between-group difference narrowed over time. The effect appeared specific to irritability, as Connors and CBCL scores showed no significant change. Tolerability was good; participants in the dextromethorphan group had no serious adverse events and fewer reported side effects than in the placebo group.

CARLAT TAKE
We’ve needed safer medications than risperidone and valproate for stimulant-refractory irritability in ADHD, so it’s refreshing to see a potentially safer adjunct studied. This trial is tiny, and the design does not lend itself to a dose-response analysis, but the signal is notable—dextromethorphan reduced irritability quickly and specifically, without touching core ADHD symptoms. While promising, we need bigger, longer studies, and additional caution since dextromethorphan is often misused.