Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood and can profoundly affect the academic achievement, well-being, and social interactions of children; the American Academy of Pediatrics first published clinical recommendations for the diagnosis and evaluation of ADHD in children in 2000; recommendations for treatment followed in 2001.

https://pediatrics.aappublications.org/content/pediatrics/early/2019/09/26/peds.2019-2528.full.pdf

ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group.

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European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD.

The Roles of Dopamine and Noradrenaline in the Pathophysiology and Treatment of Attention-Deficit/ Hyperactivity Disorder

Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework.

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A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque.

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce.

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European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

Objective This study compared the efficacy of guanfacine extended release (GXR), a selective α 2A -adrenoceptor agonist, with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method This double-blind, 9-week, dose-ranging, parallel-design, multicenter trial randomized 6- to 17-year-olds with ADHD to once-daily oral GXR in 1 -, 2-, 3-, and 4-mg doses or placebo. Primary outcome was change in total ADHD Rating Scale–IV score from baseline to endpoint. Secondary outcomes included changes in scores of hyperactive/impulsive and inattentive subscales; clinician and parent ratings; duration of clinical effect; and safety measures. Results Statistically significant reductions in ADHD Rating Scale-IV scores were observed from baseline to endpoint at all doses of GXR, with effect sizes ranging from 0.43 to 0.62. In subjects receiving GXR, mean heart rate and systolic and diastolic blood pressure decreased as the dose of GXR increased and then returned toward baseline during the dose-maintenance and dose-tapering phases of the trial. Most frequent treatment-emergent adverse events (≥ 5%) were somnolence, headache, fatigue, sedation, dizziness, irritability, upper abdominal pain, and nausea. Somnolence, sedation, and fatigue adverse events emerged within the first 2 weeks of dosing and generally resolved by study end. Conclusions Guanfacine extended-release was effective in reducing symptoms of ADHD. Adverse events were mild to moderate, did not interfere with improvements in attention, and rarely led to discontinuation.

Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial.

Introduction:Guanfacine is a noradrenergic agonist that is believed to improve symptoms of attention-deficit/hyperactivity disorder (ADHD) through selective actions at α2A-adrenoceptors in the prefrontal cortex. A recent double-blind, multicenter trial supports the efficacy and safety of guanfacine extended release (GXR) for pediatric ADHD. This long-term, open-label extension was conducted to study the safety profile and effectiveness of GXR for up to 2 years.Methods:Subjects were 240 children 6–17 years of age with a diagnosis of ADHD who participated in the preceding randomized trial. GXR was initiated at 2 mg/day and titrated as needed in 1-mg increments to a maximum of 4 mg/day to achieve optimal clinical response.Results:The most common adverse events were somnolence (30.4%), headache (26.3%), fatigue (14.2%), and sedation (13.3%). Somnolence, sedation, and fatigue were usually transient. Cardiovascular-related adverse events were uncommon, although small reductions in mean blood pressure and pulse rate were evident at monthly visits. ADHD Rating Scale, Version IV, total and subscale scores improved significantly from baseline to endpoint for all dose groups (P<.001 for all comparisons, intent-to-treat population).Conclusion:Long-term treatment with GXR was generally safe for up to 24 months of treatment, and effectiveness was maintained over this treatment period.

Jessica Donahue

Papers

Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial.

Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD.