Adherence to Clinical Guidelines for Dose Finding and Monitoring Methylphenidate Use: A Medical Record Audit in Child and Adolescent Mental Health Care and Pediatric Settings.

Background: Guideline adherence is important to ensure optimal and safe use of methylphenidate for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). We investigated adherence to Dutch guidelines regarding dosing and monitoring of methylphenidate in child and adolescent mental health care and pediatric treatment settings. Methods: Five hundred six medical records of children and adolescents were investigated in 2015 and 2016. We assessed adherence to the following guideline recommendations: (1) at least four visits during the dose-finding phase; (2) monitoring thereafter at least every 6 months; (3) measuring height and weight at least annually; and (4) the use of validated questionnaires to assess treatment response. Pearson's chi-squared test statistics were used to examine differences between settings. Results: Only a small portion of patients had at least four visits during the dose-finding phase (5.1% in the first 4 weeks to 12.4% in the first 6 weeks). Also, less than half of the patients (48.4%) were seen at least every 6 months. Height was recorded at least annually in 42.0% of patients, weight in 44.9%, and both recorded in a growth chart in 19.5%. Questionnaires to assess treatment response were only used in 2.3% of all visits. When comparing both settings, more patients in the pediatric settings were seen every 6 months, although height and weight were recorded more often in the mental health care setting. Conclusion: Overall, guideline adherence was low. Training of clinicians and adding guideline recommendations to electronic medical records templates may improve adherence. Additionally, we should aim to close the gap between guidelines and clinical practice by looking critically at the feasibility of guidelines.

Emotion recognition profiles in clusters of youth based on levels of callous-unemotional traits and reactive and proactive aggression.

Youth with disruptive behavior showing high callous-unemotional (CU) traits and proactive aggression are often assumed to exhibit distinct impairments in emotion recognition from those showing mainly reactive aggression. Yet, reactive and proactive aggression and CU traits may co-occur to varying degrees across individuals. We aimed to investigate emotion recognition in more homogeneous clusters based on these three dimensions. In a sample of 243 youth (149 with disruptive behavior problems and 94 controls) aged 8-18 years, we used model-based clustering on self-report measures of CU traits and reactive and proactive aggression and compared the resulting clusters on emotion recognition (accuracy and response bias) and working memory. In addition to a Low and Low-Moderate symptom cluster, we identified two high CU clusters. The CU-Reactive cluster showed high reactive and low-to-medium proactive aggression; the CU-Mixed cluster showed high reactive and proactive aggression. Both CU clusters showed impaired fear recognition and working memory, whereas the CU-Reactive cluster also showed impaired recognition of disgust and sadness, partly explained by poor working memory, as well as a response bias for anger and happiness. Our results confirm the importance of CU traits as a core dimension along which youth with disruptive behavior may be characterized, yet challenge the view that high CU traits are closely linked to high proactive aggression per se. Notably, distinct neurocognitive processes may play a role in youth with high CU traits and reactive aggression with lower versus higher proactive aggression.

Clinicians' Adherence to Guidelines When Initiating Methylphenidate Treatment.

Aims: Between 2008 and 2012, the number of children and adolescents in the Netherlands who received methylphenidate prescriptions increased by 35.6%. We determined guideline adherence regarding the assessment of attention-deficit/hyperactivity disorder (ADHD) and rates of off-label use in those 2 years. We also compared adherence to guidelines between mental health and pediatrics settings. Methods: We conducted a medical file audit of 506 children or adolescents who had received a first methylphenidate prescription in 2008 (n = 208) or 2012 (n = 298) across mental health (n = 333) and pediatrics outpatient clinics (n = 173) in the Netherlands and assessed adherence to seven guideline recommendations. Results: We did not find significant differences between 2008 and 2012 regarding the mean adherence to the seven recommendations (43% vs. 45%) or the percentage of off-label use (35% vs. 30%). Best adherence rates (over the years 2008 and 2012 combined) concerned the assessment of comorbidities (89%) and the involvement of teachers in the diagnostic process (75%). Least frequently adhered to were assessing ADHD severity (1%), the use of a (semi-)structured parent interview (16%), and providing psycho-education to parents (42%) or teachers (1%). Mental health settings showed better adherence than pediatrics settings (over the years 2008 and 2012 combined) concerning the use of (semi-)structured parent interviews (22% vs. 3.1%), having a separate diagnostic session directed at the child (81% vs. 63%), assessment of comorbidities (95% vs. 76%), and providing psycho-education to parents (51% vs. 24%). Conclusions: There was neither a decrease in adherence to guidelines nor an increase in off-label use between 2008 and 2012. However, there is ample room for improvement regarding guideline adherence.

Polygenic risk scores for antisocial behavior in relation to amygdala morphology across an attention deficit hyperactivity disorder case-control sample with and without disruptive behavior.

Antisocial and aggressive behaviors show considerable heritability and are central to disruptive behavior disorders (DBDs), but are also frequently observed in attention deficit hyperactivity disorder (ADHD). While the amygdala is implicated as a key neural structure, it remains unclear whether common genetic variants underlie this brain-behavior association. We hypothesized that polygenic (risk) scores for antisocial and aggressive behaviors (ASB-PRS) would be related to amygdala morphology. Using the Broad Antisocial Behavior Consortium genome-wide association study (GWAS; mostly population based cohorts), we calculated ASB-PRS in the NeuroIMAGE I ADHD case-control sample with varying levels of DBD symptomatology (n=679 from 379 families, aged 7 - 29). We first investigated associations of several ASB-PRS p value thresholds with the presence of DBD symptoms and self-reported antisocial behavior (ASB) to determine the threshold for further analyses. This PRS was then related to amygdala volume and shape using regression and vertex-wise analyses. Our results showed associations of ASB-PRS with the presence of DBD symptoms, self-reported ASB, and left basolateral amygdala shape, independent of ADHD symptom severity and ADHD-PRS, with a relative outward displacement of the vertices. No associations of ASB-PRS, DBD symptoms or self-reported ASB with amygdala volume were found. Our results indicate that genetic risk for antisocial and aggressive behaviors is related to amygdala shape alterations, and point to genetic sharing across different DBD and ASB and aggression-related phenotypes as a spectrum of genetically related quantitative traits. Additionally, our findings support the utility of vertex-based shape analyses in genetic studies of ASB, aggression, and DBDs.

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior.

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control.

Specific cortical and subcortical alterations for reactive and proactive aggression in children and adolescents with disruptive behavior.

Maladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated associations between aggression subtypes, CU traits and ADHD symptoms in predefined regions of interest. T1-weighted magnetic resonance images were acquired from 158 children and adolescents with disruptive behavior (ODD/CD) and 96 controls in a multi-center study (aged 8-18). Aggression subtypes were assessed by questionnaires filled in by participants and their parents. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool. Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models. Proactive aggression was negatively associated with amygdala volume (b = -10.7, p = 0.02), while reactive aggression was negatively associated with insula volume (b = -21.7, p = 0.01). No associations were found with CU traits or ADHD symptomatology. Classical group comparison showed that children and adolescents with disruptive behavior had smaller volumes than controls in (bilateral) vmPFC (p = 0.003) with modest effect size and a reduced shape in the anterior part of the left ventral striatum (p = 0.005). Our study showed negative associations between reactive aggression and volumes in a region involved in threat responsivity and between proactive aggression and a region linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure which may provide useful insights for clinical practice.

Executive functioning and emotion recognition in youth with oppositional defiant disorder and/or conduct disorder.

Objectives: Executive functioning and emotion recognition may be impaired in disruptive youth, yet findings in oppositional defiant disorder (ODD) and conduct disorder (CD) are inconsistent. We examined these functions related to ODD and CD, accounting for comorbid attention-deficit/hyperactivity disorder (ADHD) and internalising symptoms.Methods: We compared executive functioning (visual working memory, visual attention, inhibitory control) and emotion recognition between youth (8-18 years old, 123 boys, 55 girls) with ODD (n = 44) or CD (with/without ODD, n = 48), and healthy controls (n = 86). We also related ODD, CD, and ADHD symptom counts and internalising symptomatology to all outcome measures, as well as executive functioning to emotion recognition.Results: Visual working memory and inhibitory control were impaired in the ODD and CD groups versus healthy controls. Anger, disgust, fear, happiness, and sadness recognition were impaired in the CD group; only anger recognition was impaired in the ODD group. Deficits were not explained by comorbid ADHD or internalising symptoms. Visual working memory was associated with recognition of all basic emotions.Conclusions: Our findings challenge the view that neuropsychological impairments in youth with ODD/CD are driven by comorbid ADHD and suggest possible distinct neurocognitive mechanisms in CD versus ODD.

Effects of Discontinuing Methylphenidate on Strengths and Difficulties, Quality of Life and Parenting Stress.

Objectives: To study the effects of discontinuation of long-term methylphenidate use on secondary outcome measures of strengths and difficulties, quality of life (QoL), and parenting stress. Methods: Ninety-four children and adolescents aged 8 to 18 years who had used methylphenidate for over 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg extended release methylphenidate) or to gradual withdrawal over 3 to 4 weeks placebo. We used mixed models for repeated measures to investigate effects on parent, teacher, and child ratings of hyperactivity/inattention and comorbid symptoms with the Strengths and Difficulties Questionnaire (SDQ), investigator- and teacher-rated oppositional symptoms (Conners Teacher Rating Scale-Revised: short form [CTRS-R:S]), and parent-rated aggression with the Retrospective Modified Overt Aggression Scale. QoL was assessed with the Revised Questionnaire for Children and Adolescents to record health-related quality of life and parenting stress with the Nijmegen Parental Stress Index. Results: Hyperactivity/inattention scores from the parent- and teacher-rated SDQ (difference in mean change over time of respectively: -1.1 [95% confidence interval, CI, -2.0 to -0.3]; p = 0.01; -2.9 [95% CI -2.9 to -0.7; p = 0.01]) and oppositional scores of the teacher-rated CTRS-R:S (difference in mean change -1.9 95% CI [-3.1 to -0.6; p < 0.01]) deteriorated to a significantly larger extent in the discontinuation group than in the continuation group. We did not find effects on other symptom domains, aggression, QoL, and parenting stress after discontinuation of methylphenidate. Conclusion: Our study suggests beneficial effects of long-term methylphenidate use beyond 2 years for oppositional behaviors in the school environment. Similarly, beneficial effects were found on hyperactivity-inattention symptoms as rated by parent and teacher scales, confirming our primary study on investigator ratings of attention-deficit/hyperactivity disorder. However, discontinuation of methylphenidate did not appear to have impact on other comorbid problems or aspects of the child's or parental functioning.

Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study.

OBJECTIVE: The benefits of long-term use of methylphenidate treatment in children and adolescents with attention deficit hyperactivity disorder (ADHD), as frequently prescribed in clinical practice, are unclear. The authors investigated whether methylphenidate remains beneficial after 2 years of use. METHODS: Ninety-four children and adolescents (ages 8-18 years) who had been treated in regular care with methylphenidate for more than 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg/day of extended-release methylphenidate) or gradual withdrawal over 3 weeks, to 4 weeks of placebo. The primary outcome measure was the investigator-rated ADHD Rating Scale (ADHD-RS); secondary outcome measures were the investigator-rated Clinical Global Impressions improvement scale (CGI-I) and the Conners' Teacher Rating Scale-Revised: Short Form (CTRS-R:S). Continuous ratings were analyzed with mixed model for repeated measures analyses, and the CGI-I with a chi-square test. RESULTS: The mean ADHD-RS scores at baseline for the continuation and discontinuation groups, respectively, were 21.4 (SD=9.7) and 19.6 (SD=8.9); after 7 weeks, the mean scores were 21.9 (SD=10.8) and 24.7 (SD=11.4), with a significant between-group difference in change over time of -4.6 (95% CI=-8.7, -0.56) in favor of the group that continued methylphenidate treatment. The ADHD-RS inattention subscale and the CTRS-R:S ADHD index and hyperactivity subscale also deteriorated significantly more in the discontinuation group. The CGI-I indicated worsening in 40.4% of the discontinuation group, compared with 15.9% of the continuation group. CONCLUSIONS: Continued treatment with methylphenidate remains effective after long-term use. Some individual patients may, however, be withdrawn from methylphenidate without deterioration. This finding supports guideline recommendations that patients be assessed periodically to determine whether there is a continued need for methylphenidate treatment.