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

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.

Individualized medicine (Erder et al, 2012) using biomarkers such as neuroimaging (‘third-generation’ or ‘next-generation’ neuroimaging) is increasingly important in psychiatry (Borgwardt

and Fusar-Poli, 2012). The psychostimulant methylphenidate hydrochloride (MPH) is an effective first-line treatment for children with attention-deficit hyperactivity disorder (ADHD)

(Buitelaar and Medori, 2010). However, ~30% of children with ADHD do not respond to MPH (Wilens et al, 2008) and experience no benefit or only adverse side effects (Cho et al, 2007; Rapport

et al, 1994). Moreover, although positron emission tomography studies of MPH exposure suggest that catecholamine dysfunction at least partially mediates the behavioral and cognitive features

of ADHD (Hannestad et al, 2010; Krause, 2008; Volkow et al, 2002), how MPH affects the nervous system remains unclear, especially over long periods.

Several studies have attempted to predict MPH efficacy using clinical characteristics including age (Buitelaar et al, 1995; Zeiner et al, 1999), IQ (Buitelaar et al, 1995), symptoms,

disorder severity (Buitelaar et al, 1995; Zeiner et al, 1999), and neuropsychological test scores (Lee et al, 2009). Recently, more objective biomedical predictors (Hermens et al, 2006) of

brain function (An et al, 2013; Cho et al, 2007; Ilgin et al, 2001; la Fougere et al, 2006; Sangal and Sangal, 2004; Schweitzer et al, 2003) have been used (see also Supplementary

Materials). Most neuroimaging MPH trials have included previously medicated subjects. However, recent studies have revealed differences in brain structure between drug-naïve and previously

treated ADHD patients (Frodl and Skokauskas, 2012; Shaw et al, 2009).

Here, we primarily aimed to develop an objective marker using near-infrared spectroscopy (NIRS) that predicts the efficacy of continuous MPH administration for children with ADHD. NIRS

imaging is safe, portable, and allows easy examination of subjects in a natural sitting position (Ishii-Takahashi et al, 2013; Monden et al, 2012; Takizawa et al, 2008). To elicit prefrontal

activation, we used the stop signal task (SST), an inhibitory task that reflects the pathophysiology of ADHD (Hart et al, 2013; Rubia et al, 2014). The single-dose MPH administration phase

used a randomized, double-blind, placebo-controlled, crossover design, and the subsequent outcome was assessed in a 4-to-8-week open trial and 1-year follow-up. To our knowledge, no previous

study has followed patients for 1 year to predict the effect of MPH using neuroimaging. We hypothesized that prefrontal activation at baseline assessment, or the difference in NIRS signal

between a single administration of MPH and the baseline assessment, would predict clinical improvement after mid-term (4-to-8-week) and long-term (1-year) MPH treatment in drug-naïve

patients with ADHD. Notably, we divided children with ADHD into those who had not received any medication (drug naïve) and those who had received chronic treatment with MPH (non-naïve)

because the NIRS signals at baseline may be altered by previous MPH treatment.

Our secondary purpose was to test whether multiple NIRS measurements are useful in monitoring prefrontal activation during continuous MPH treatment in children with ADHD. For this purpose,

we recruited healthy controls (HCs) and monitored their NIRS signals at multiple times without any intervention. Then, we tested the effect of MPH treatment on the NIRS signals after

single-dose, mid-term, and long-term administration in ADHD children.

We examined 30 children with ADHD (mean age: 8.6±1.4 years) and 20 age-, sex-, and IQ-matched HCs (Table 1), all recruited from an outpatient unit at the University of Tokyo Hospital, who

consisted of two groups: drug-naïve ADHD (NAÏVE) and ADHD patients taking MPH for at least 1 month (NON-NAÏVE; Figures 1 and 2). HCs underwent multiple neuroimaging measurements without any

clinical intervention.

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.

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.

Child psychiatrists diagnosed ADHD through comprehensive clinical assessments and in accordance with the DSM-IV. Current and lifetime DSM-IV diagnoses were determined by a consensus decision

based on the results of independent clinical interviews, clinical data, and the Mini-International Neuropsychiatric Interview for Children and Adolescents (Otsubo et al, 2005). Additional

inclusion criteria were age (6–12 years) and IQ (above 70) determined with the Wechsler Children Intelligence Scale, 3rd edition. The exclusion criteria are described in Supplementary

Materials.

The ADHD Rating Scale IV (ADHD-RS-IV) was used to assess ADHD symptoms (DuPaul et al, 1998). Problematic behaviors were measured from parent reports using the Child Behavior Checklist (CBCL;

Achenbach et al, 1991).

After baseline assessment before MPH administration (Phase 1), we conducted a double-blind, placebo-controlled, crossover, prospective trial of single-dose MPH administration (Phase 2), with

a subsequent 4-to-8-week open trial (Phase 3; Figure 1). We then conducted a 1-year follow-up (Phase 4) as an ancillary study. Prefrontal hemodynamics were measured in NAÏVE and NON-NAÏVE

using NIRS at Phase 1, Phase 2 (two times after a single dose of MPH or placebo), and Phase 3. NAÏVE was also assessed at Phase 4. We evaluated the NIRS signals of HCs at the same time

points used for NAÏVE (Figure 1). For details about the repeated measurements in HCs, see Supplementary Materials.

The target sample size for this study was ~20 children (NAÏVE) for the primary outcome, after accounting for dropout cases. We estimated the sample size based on an optimal design for

functional brain imaging (Carter et al, 2008).

All children and parents provided written informed consent after receiving a complete explanation of the study, according to the Declaration of Helsinki. The institutional review board (IRB)

and ethical committee of the University of Tokyo Hospital approved this study (approval number: P2007009 and 630-8). This trial is registered as number UMIN000001270.

A schematic diagram of the trial protocol is shown in Figure 1. In Phase 1, NON-NAÏVE was instructed to stop taking MPH for 1 week before the single-dose trial began.

In Phase 2, placebo or MPH (18 mg; MPH osmotic-release oral system (OROS), Concerta) was administered at 1-week intervals. Subjects received a blinded capsule (placebo or MPH) in the front

of the investigator (AI-T) 5 h before the NIRS session.

In Phase 3, the optimal dose was administered for 4 weeks. After a 1-week washout period, the NON-NAÏVE group was administered the same amount of MPH that they were taking before

participating in the trial. Because the NON-NAÏVE group did not experience a titration period, the length of their open-label trial was 4 weeks. In the NAÏVE group, the dose was determined

from the results of the controlled medication trial described below. The ADHD-RS-IV and side-effect rating scale were assessed weekly. A psychiatrist reviewed the data each week to determine

the best MPH dose. MPH was titrated to an optimal response from an initial dose of 18 mg. During titration, the dosage was increased by 9 mg at weekly visits. When side effects occurred,

the dose was reduced to a level where no side effects occurred, which then was considered the optimal dose. After the titration period, the NAÏVE group was administered the optimal dose for

4 weeks. After titration, the optimal dose for each patient was determined (mean dose: 25.4 mg, 0.91 mg/kg; SD: 5.9; median: 27). Participants continued receiving the optimal dose of MPH for

4 weeks (mean duration including titration: 5.45 weeks; SD: 1.29; median: 5).

Phase 4 was a 1-year follow-up as an ancillary study. We followed NAÏVE participants who continued MPH administration for at least 1-year (mean duration: 14.7 months; SD: 2.3; median: 14.5)

after the 4-to-8-week open trial. The same child psychiatrist who evaluated the children in the baseline assessment evaluated the severity and clinical response after 1-year-MPH

administration using the Clinical Global Impressions-Severity (CGI-S). The NAÏVE stopped taking MPH for 1 week before undergoing the last NIRS measurement.

The washout period, timing of MPH administration, titration procedure, and mean dose of MPH are described in the Supplementary Materials.

We used NIRS to measure changes in the mean oxygenated hemoglobin concentration ([oxy-Hb]) in the bilateral inferior frontal cortex (IFC: Supplementary Figure S1) during the SST, which

served as an explanatory variable. The procedures for the SST and NIRS measurements are described in detail in Supplementary Materials and Supplementary Figure S2, and in our previous report

(Ishii-Takahashi et al, 2013).

We also used the CGI-S (Guy, 1976) scores after 4-to-8-week administration (Phase 3) and 1-year administration (Phase 4) of the optimal dose of MPH as outcome measures (Figure 1). We did not

use the ADHD-RS-IV as a primary outcome measure in the clinical trial registry because ADHD-RS-IV was translated to Japanese in 2007 and has not been validated in Japanese patients. A

detailed explanation about the adoption of CGI-S as an assessment tool of primary outcome was reported in Supplementary Materials. The child psychiatrist (AI-T) reviewed the severity and

clinical response as assessed by CGI-S (Buitelaar et al, 1995; Cho et al, 2007).

For the primary analysis, regression analysis was conducted to examine whether [oxy-Hb] measured at the baseline assessment or Δ[oxy-Hb] (single dose of MPH minus baseline assessment)

predicted CGI-S scores after the 4-to-8-week open trial and after 1 year of MPH administration.

For secondary analysis, we examined at Phase 1, whether brain function differed among NAÏVE, NON-NAÏVE, and HCs; at Phase 2, whether a single dose of MPH or placebo-affected [oxy-Hb]; at

Phase 3, whether brain function differed among NAÏVE, NON-NAÏVE, and HCs during the 4-to-8-week administration of MPH; and at Phase 4, whether administration of MPH for 1-year affected

[oxy-Hb] after washout.

After baseline assessments, a study investigator (AI-T) assigned the participants to an intervention. An IRB member (Y.A.) generated a random allocation sequence to blind participants

assigned an intervention and stratified the participants into two groups according to their medications. The patients were randomly assigned in a 1:1 ratio to one of the two groups. In the

first group, the patients first received a single dose of MPH, and 1 week later, they received a single dose of placebo. In the second group, the order was reversed. Participants, care

providers, and investigators were double-blinded to the intervention. Placebos were sucrose capsules similar to the MPH capsules. The investigators were informed of patient assignments after

Phase 3 was completed.

Statistical analyses were conducted after completing the trials and opening the allocation; the analyses followed the intention-to-treat principle. All reported P-values are two-tailed.

Clinical and behavioral results were considered significant at P