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Effect of Methylphenidate on Resting-State Connectivity in Adolescents With a Disruptive Behavior Disorder: A Double-Blind Randomized Placebo-Controlled fMRI Study.

ABSTRACT: Some studies suggest that methylphenidate (MPH) might be an effective treatment for antisocial and aggressive behavior in adolescence. However, little is known about the mechanism of action of MPH in adolescents with this kind of psychopathology. MPH is a dopamine and norepinephrine reuptake inhibitor and thus it is likely to affect dopaminergic mesocorticolimbic pathways. This is the first study to investigate the effect of MPH on resting-state connectivity of three mesolimbic seed regions with the rest of the brain in clinical referred male adolescents with a disruptive behavior disorder (DBD). Thirty-six male DBD adolescents and 31 male healthy controls (HCs) were included. DBD subjects were randomly allocated to a single dose of MPH (DBD-MPH, n = 20) or placebo (DBD-PCB, n = 16). Seed-based resting-state functional connectivity of the nucleus accumbens (NAcc), amygdala, and ventral tegmental area (VTA) with the rest of the brain was compared between groups. The NAcc seed showed increased connectivity in DBD-PCB compared to HC with the occipital cortex, posterior cingulate cortex (PCC), precuneus, and inferior parietal lobule (IPL) and increased connectivity in DBD-PCB compared to DBD-MPH with occipital cortex, IPL, and medial frontal gyrus. The amygdala seed showed increased connectivity in DBD-PCB compared to HC with the precuneus and PCC. The VTA seed showed increased connectivity in the DBD-MPH compared to the DBD-PCB group with a cluster in the postcentral gyrus and a cluster in the supplementary motor cortex/superior frontal gyrus. Both NAcc and amygdala seeds showed no connectivity differences in the DBD-MPH compared to the HC group, indicating that MPH normalizes the increased functional connectivity of mesolimbic seed regions with areas involved in moral decision making, visual processing, and attention.

SUBMITTER: Pape L

PROVIDER: S-EPMC8247590 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Methylphenidate (MPH) is efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD), but there are no data about the efficacy and safety of its new formulation (ORADUR®-MPH extended release, ORADUR-MPH) in patients with ADHD, which is the study objective. Method: This was a Phase III, multicenter, randomized, double-blind, placebo-controlled, two-way crossover clinical trial. One hundred children and adolescents with a clinical diagnosis of ADHD (72.7% male) received at least one dose of ORADUR-MPH or a placebo during the 2-week treatment period of each phase. The primary efficacy measure was the Swanson, Nolan, and Pelham-IV-teacher (SNAP-IV-T) form. Secondary efficacy measures included the SNAP-IV-parent form, the Clinical Global Impression: ADHD-Severity score, the Conner's Teacher's Rating Scale score, and the investigator's rating for 18 Diagnostic and Statistical Manual of Mental Disorders, 5th edition ADHD symptoms. In addition, data related to vital signs, body weight, physical examination, laboratory testing, and adverse events (AEs) were also collected. All data were analyzed on an intent-to-treat basis. Results: Without adjusting for differences in demographics and baseline measures, both treatment groups showed significant reductions in ADHD and oppositional defiant disorder symptoms after a 2-week treatment with greater effect sizes (Cohen's d) in the ORADUR-MPH group (Cohen's d ranging from -0.41 to -1.64; placebo, Cohen's d ranging from -0.26 to -1.18), except for oppositional symptoms, regardless of the informants. For the primary efficacy measure, ORADUR-MPH was significantly superior to the placebo, as evidenced by lower values for and greater reductions in the SNAP-IV-T scores at the endpoint (Cohen's d = -0.16, p = 0.005) and from baseline to the endpoint (Cohen's d = -0.19, p = 0.006), respectively. There were no serious AEs during the clinical study period. The most frequently observed AE was decreased appetite (49.1%). Most physical and laboratory test variables remained within the normal range. Conclusions: Once-daily ORADUR-MPH is an effective, well-tolerable, and safe treatment for children and adolescents with ADHD. ClinicalTrials.gov number, NCT02450890.

Dataset Information

Effect of Methylphenidate on Resting-State Connectivity in Adolescents With a Disruptive Behavior Disorder: A Double-Blind Randomized Placebo-Controlled fMRI Study.

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