Neuroimaging-Aided Prediction of the Effect of Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder: A Randomized Controlled Trial

Abstract

Although methylphenidate hydrochloride (MPH) is a first-line treatment for children with attention-deficit hyperactivity disorder (ADHD), the non-response rate is 30%. Our aim was to develop a supplementary neuroimaging biomarker for predicting the clinical effect of continuous MPH administration by using near-infrared spectroscopy (NIRS). After baseline assessment, we performed a double-blind, placebo-controlled, crossover trial with a single dose of MPH, followed by a prospective 4-to-8-week open trial with continuous MPH administration, and an ancillary 1-year follow-up. Twenty-two drug-naïve and eight previously treated children with ADHD (NAÏVE and NON-NAÏVE) were compared with 20 healthy controls (HCs) who underwent multiple NIRS measurements without intervention. We tested whether NIRS signals at the baseline assessment or ΔNIRS (single dose of MPH minus baseline assessment) predict the Clinical Global Impressions-Severity (CGI-S) score after 4-to-8-week or 1-year MPH administration. The secondary outcomes were the effect of MPH on NIRS signals after single-dose, 4-to-8-week, and 1-year administration. ΔNIRS significantly predicted CGI-S after 4-to-8-week MPH administration. The leave-one-out classification algorithm had 81% accuracy using the NIRS signal. ΔNIRS also significantly predicted CGI-S scores after 1 year of MPH administration. For secondary analyses, NAÏVE exhibited significantly lower prefrontal activation than HCs at the baseline assessment, whereas NON-NAÏVE and HCs showed similar activation. A single dose of MPH significantly increased activation compared with the placebo in NAÏVE. After 4-to-8-week administration, and even after MPH washout following 1-year administration, NAÏVE demonstrated normalized prefrontal activation. Supplementary NIRS measurements may serve as an objective biomarker for clinical decisions and monitoring concerning continuous MPH treatment in children with ADHD.

Figure 1

Schematic diagram of the trial protocol. NAÏVE and NON-NAÏVE underwent baseline assessment (Phase 1), a single-dose trial (Phase 2), and a 4-to-8-week open trial (Phase 3). NAÏVE participants also underwent a 1-year follow-up (Phase 4). NAÏVE was evaluated by NIRS in five sessions (Phase 1: 1 session, Phase 2: 2 sessions, Phase 3: 1 session, and Phase 4: 1 session). NON-NAÏVE was evaluated by NIRS signal in four sessions (Phase 1: 1 session, Phase 2: 2 sessions, and Phase 3: 1 session). We evaluated the NIRS signal of HCs, who did not take MPH, at the same intervals and times as NAÏVE to detect the effects of the repeated measurement. ADHD, attention-deficit hyperactivity disorder; HCs, healthy controls; MPH, methylphenidate hydrochloride; NAÏVE, ADHD-drug NAÏVE; NIRS, near-infrared spectroscopy; NON-NAÏVE, ADHD patients who had taken methylphenidate for several months.

Figure 2

Trial profile. For the primary outcome, only NAÏVE (N=21) was assessed. For the secondary outcome, NAÏVE (N=22) and NON-NAÏVE (N=8) groups were evaluated for the effect of the single-dose trial. NAÏVE (N=21), NON-NAÏVE (N=8), and HCs (N=20) were evaluated in the analysis for the effect of the 4-to-8-week open trial. For the ancillary analysis, naïve was analyzed to determine the predictor of CGI-S after 1 year of MPH administration (N=14). NAÏVE (N=14) and HCs (N=15) were analyzed for the effect of 1 year of MPH administration after washout. (a) After participants were matched for age, sex, IQ, and SST performance among the NAÏVE, NON-NAÏVE, and HCs, 20 members of HCs were selected. ADHD, attention-deficit hyperactivity disorder; HCs, healthy controls; MPH, methylphenidate hydrochloride; NAÏVE, ADHD-drug naïve; NIRS, near-infrared spectroscopy; NON-NAÏVE, ADHD patients who had taken methylphenidate for several months; SST, stop signal task.

Figure 3

Results for primary outcomes: predictor of CGI-S in NAÏVE. (a) Correlation between CGI-S scores (4-to-8-week open trial: 2, borderline mentally ill (N=4); 3, mildly ill (N=12); 4, moderately ill (N=5)) and Δ[oxy-Hb] (single dose of MPH minus baseline assessment) in the LIFC (β=−0.519, P=0.0160). (b) Correlation between CGI-S (after 1-year follow-up: 2, borderline mentally ill (N=6); 3, mildly ill (N=6); 4, moderately ill (N=2)) and Δ[oxy-Hb] (single dose of MPH minus baseline assessment) in the LIFC (β=−0.716, P=0.0040). ADHD, attention-deficit hyperactivity disorder; CGI-S, Clinical Global Impression-Severity; HCs, healthy controls; LIFC, left inferior frontal cortex; MPH, methylphenidate hydrochloride; NAÏVE, ADHD-drug naïve; NIRS, near-infrared spectroscopy; NON-NAÏVE, ADHD patients who had taken methylphenidate for several months; [oxy-Hb], oxygenated hemoglobin concentration; RIFC, right inferior frontal cortex.

Figure 4

Results for secondary outcomes: effects of the 4-to-8-week open trial of MPH, effects of a single-dose trial, and effects of 1 year of MPH administration observed after washout. (a) At the baseline assessment (RIFC, Bonferroni-corrected P=0.0455; LIFC, Bonferroni-corrected P=0.0908). (b) Differences in [oxy-Hb] changes during the SST in the single-dose trial between MPH and placebo treatments in NAÏVE (RIFC: Bonferroni-corrected P=0.0281). (c) Differences in [oxy-Hb] changes during the SST between the HCs and ADHD groups after the 4-to-8-week open trial. Error bars indicate 95% CI. (d) Differences in [oxy-Hb] changes during SST between the HCs and NAÏVE after 1-year follow-up (baseline assessment: Bonferroni-corrected P=0.0121; after 1-year follow-up: Bonferroni-corrected P=0.6386). Error bars indicate 95% CI. ADHD, attention-deficit hyperactivity disorder; CGI-S, Clinical Global Impression-Severity; HCs, healthy controls; LIFC, left inferior frontal cortex; MPH, methylphenidate hydrochloride; NAÏVE, ADHD-drug naïve; NIRS, near-infrared spectroscopy; NON-NAÏVE, ADHD patients who had taken methylphenidate for several months; [oxy-Hb], oxygenated hemoglobin concentration; RIFC, right inferior frontal cortex; SST, stop signal task.