Electrophysiological and Clinical Predictors of Methylphenidate, Guanfacine, and Combined Treatment Outcomes in Children With Attention-Deficit/Hyperactivity Disorder

Abstract

Objective: The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.

Method: A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity.

Results: Higher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R²= 0.34-0.41) as clinical measures alone (R² = 0.14-.21).

Conclusion: We identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD.

Clinical trial registration information: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; https://clinicaltrials.gov; NCT00429273.

Keywords: attention-deficit/hyperactivity disorder; electroencephalography; guanfacine; methylphenidate; predictor.

Figure 1.. Pre-treatment predictors of change in ADHD severity between pre-treatment and end of treatment.

Notes: This graph shows predictors showing significant (p≤.01) or trend-level (p≤.05) effects across treatments or interaction effects with treatment group. Higher scores of the treatment outcome measure reflect greater improvement, so positive values of beta coefficients indicate that higher values of the parameter are associated with greater improvement. Full results are presented in Supplementary Material (Table S1). SWAN scores were reverse-coded, such that higher scores represent higher ADHD severity. 95% CI not including 0 indicate p<.05. Abbreviations: CI, 95% confidence interval; COMB, combined treatment group; DMPH, d-methylphenidate monotherapy group; GUAN, guanfacine monotherapy group; MASC, Multidimensional Anxiety Scale for Children scales; SWAN, Strengths and Weaknesses of ADHD symptoms and Normal Behavior scales.

Figure 2.. Bar graphs showing the mean and standard error of pre-treatment beta power measures divided by binary treatment response (≥30% ADHD-RS improvement) in each treatment group.

Notes: Asterisks refer to significant (**p≤.01) or trend-level (*p<.05) predictive effects within each group based on results of logistic regressions. Black squared brackets and arrows reflect differences between responders and non-responders within each treatment group. Gray squared brackets and arrows reflect differences in the predictive effects between treatment groups. Abbreviations: COMB, combined treatment group; DMPH, d-methylphenidate monotherapy group; GUAN, guanfacine monotherapy group.

Figure 3.. Variance explained (R²) in multivariate prediction models of continuous treatment improvement in ADHD-RS by medication group.

Notes: **p≤.01; *p<.05. All models also included age as a covariate. Results for DMPH are not shown as there were no significant EEG predictors of continuous change in ADHD severity with this treatment. Abbreviations: COMB, combined treatment group; DMPH, d-methylphenidate monotherapy group; GUAN, guanfacine monotherapy group.