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.

Attention-deficit-hyperactivity disorder (ADHD) is a common neuropsychiatric disorder that impairs social, academic, and occupational functioning in children, adolescents, and adults. In patients with ADHD, neurobiologic research has shown a lack of connectivity in key brain regions, inhibitory control deficits, delayed brain maturation, and noradrenergic and dopaminergic dysfunction in multiple brain regions. The prevalence of this disorder in the United States is 6–9% in youth (i.e., children and adolescents) and 3–5% in adults. Prevalence rates for youth are similar worldwide. Children with ADHD are at greater risk than children without ADHD for substance abuse and delinquency whether or not they receive drug therapy; however, early treatment with psychoeducation as well as drug therapy and/or behavioral intervention may decrease negative outcomes of ADHD, including the rate of conduct disorder and adult antisocial personality disorder. Drug therapy is effective for all age groups, even preschoolers, and for late-onset ADHD in adults. Stimulants, such as methylphenidate and amphetamine, are the most effective therapy and have a good safety profile; although recent concerns of sudden unexplained death, psychiatric adverse effects, and growth effects have prompted the introduction of other therapies. Atomoxetine, a nonstimulant, has no abuse potential, causes less insomnia than stimulants, and poses minimal risk of growth effects. Other drug options include clonidine and guanfacine, but both can cause bradycardia and sedation. Polyunsaturated fatty acids (fish oil), acetyl-l-carnitine, and iron supplements (for youth with low ferritin levels) show promise in improving ADHD symptoms. As long-term studies show that at least 50% of youth are nonadherent with their drug therapy as prescribed over a 1-year period, longacting formulations (administered once/day) may improve adherence. Comorbid conditions are common in patients with ADHD, but this patient population can be treated effectively with individualized treatment regimens of stimulants, atomoxetine, or bupropion, along with close monitoring.

Attention-deficit-hyperactivity disorder: an update.

Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses.

OBJECTIVES Medications used to treat attention-deficit/hyperactivity disorder (ADHD) in adults have been well researched, but comparisons among drugs are hindered by the absence of direct comparative trials. Our objectives were to (1) estimate the effect size of the medications used to treat adult ADHD, (2) determine if differences in the designs of studies confound comparisons of medication efficacy, (3) quantify the evidence for differences in effect sizes among medications, and (4) see if features of study design influence estimates of efficacy. DATA SOURCES The following search engines were used: PubMed, Ovid, ERIC, CINAHL, MEDLINE, PREMEDLINE, the Cochrane database, e-psyche, and Social Sciences Abstracts. Presentations from the American Psychiatric Association and American Academy of Child and Adolescent Psychiatry meetings were reviewed. STUDY SELECTION A literature search was conducted to identify double-blind, placebo-controlled studies of ADHD in adults published in English after 1979. Only trials that used DSM-III, -III-R, or -IV ADHD criteria and followed subjects for > or = 2 weeks were selected. DATA EXTRACTION Meta-analysis regression assessed the influence of medication type and study design features on medication effects. RESULTS Nineteen trials met criteria and were included in this meta-analysis. These trials studied 13 drugs using 18 different outcome measures of hyperactive, inattentive, or impulsive behavior. After trials were stratified on the class of drug studied (short-acting stimulant vs long-acting stimulant vs nonstimulant), significant differences in effect size were observed between stimulant and nonstimulant medications (P = .006 and P = .0001, respectively, for short- and long-acting stimulants vs nonstimulants), but the effect for short-acting stimulants was not significant after correcting for study design features. The effect sizes for each drug class were similar in magnitude to what we previously reported for medication treatment studies of children with ADHD. We found significant heterogeneity of effect sizes for short-acting stimulants (P < .001) but not for other medication groups. CONCLUSIONS Although both stimulant and nonstimulant medications are effective for treating ADHD in adults, stimulant medications show greater efficacy for the short durations of treatment characteristic of placebo-controlled studies. We found no significant differences between short- and long-acting stimulant medications. Study design features vary widely among studies and can confound indirect comparisons unless addressed statistically as we have done in this study.

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A Comparison of the Efficacy of Medications for Adult Attention-Deficit/Hyperactivity Disorder Using Meta-Analysis of Effect Sizes

OBJECTIVE. With this study we assessed the efficacy and safety of an extended-release formulation of guanfacine compared with placebo for the treatment of children and adolescents with attention-deficit/hyperactivity disorder. METHODS. In this multicenter, double-blind, placebo-controlled, fixed-dosage escalation study, patients aged 6 to 17 years were randomly assigned to 1 of 3 treatment groups of guanfacine extended release (2, 3, or 4 mg/day) or placebo for 8 weeks. The primary outcome measurement was the Attention-Deficit/Hyperactivity Disorder Rating Scale IV total score. Secondary measurements included Clinical Global Impression of Improvement, Parent9s Global Assessment, Conners9 Parent Rating Scale–Revised: Short Form, and Conners9 Teacher Rating Scale–Revised: Short Form. RESULTS. A total of 345 patients were randomly assigned to placebo (n = 86) or guanfacine extended release 2 mg (n = 87), 3 mg (n = 86), or 4 mg (n = 86) treatment groups. Least-squares mean changes from baseline to the end point in Attention-Deficit/Hyperactivity Disorder Rating Scale IV total scores were significant in all groups of children taking guanfacine extended release: −16.18 in the 2-mg group, −16.43 in the 3-mg group, and −18.87 in the 4-mg group, compared with −8.48 in the placebo group. All groups of children taking guanfacine extended release showed significant improvement on hyperactivity/impulsivity and inattentiveness subscales of the Attention-Deficit/Hyperactivity Disorder Rating Scale IV, Clinical Global Impression of Improvement, Parent9s Global Assessment, Conners9 Parent Rating Scale–Revised: Short Form, and Conners9 Teacher Rating Scale–Revised: Short Form assessments compared with placebo. The most commonly reported treatment-emergent adverse events were headache, somnolence, fatigue, upper abdominal pain, and sedation. Small to modest changes in blood pressure, pulse rate, and electrocardiogram parameters were observed but were not clinically meaningful. CONCLUSIONS. Guanfacine extended release met the primary and secondary efficacy end points. It was well tolerated and effective compared with placebo.

A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder.

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.

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

We have compared fluorescent and nonfluorescent light sources for phototherapy for newborn infants with hyperbilirubinemia. Phototherapy was provided by a tungsten halogen lamp and conventional fluorescent light with identical radiant flux of 6 microW/sq cm. For 22 infants treated with the nonfluorescent lamp the mean duration of phototherapy was 33.77 hours and the mean reduction of bilirubin was 3.84 mg/100 ml/day. This did not differ significantly from infants treated with conventional fluorescent lights. The nonfluorescent light can be utilized for infants in incubators or on radiant warmers. These results provide additional support for the relationship between radiant flux as a practical measure of phototherapy dose and the clinical response of a reduction in serum bilirubin.

A comparison of fluorescent and nonfluorescent light sources for phototherapy.

Giant cell arteritis (GCA) is a severe granulomatous occlusive vasculitis affecting medium to large arteries of the head and neck.1Hunder GG. Giant cell arteritis and polymyalgia rheumatica.Med Clin North Am. 1997; 81: 195-219Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar GCA can cause intense myointimal proliferation and vessel occlusion of the ophthalmic artery, central retinal artery, and short posterior ciliary arteries leading to irreversible vision loss.2Yates M Loke YK Watts RA MacGregor AJ. Prednisolone combined with adjunctive immunosuppression is not superior to prednisolone alone in terms of efficacy and safety in giant cell arteritis: meta-analysis.Clin Rheumatol. 2014; 33: 227-236Crossref PubMed Scopus (39) Google Scholar,3Ghosh P Borg FA Dasgupta B. Current understanding and management of giant cell arteritis and polymyalgia rheumatica.Expert Rev Clin Immunol. 2010; 6: 913-928Crossref PubMed Scopus (16) Google Scholar Steroids remain the mainstay of treatment but usually require a slow taper over 1–3 years and lead to significant side effects in >80% of patients.4Mukhtyar C Guillevin L Cid MC et al.for the European Vasculitis Study Group. EULAR recommendations for the management of large vessel vasculitis.Ann Rheum Dis. 2009; 68: 318-323Crossref PubMed Scopus (479) Google Scholar The Trial of Tocilizumab in Giant Cell Arteritis (GiACTA) in 2017 demonstrated the effectiveness of the recombinant monoclonal antibody interleukin-6 inhibitor tocilizumab (TCZ) combined with accelerated prednisone taper in achieving sustained glucocorticoid-free remission in GCA patients.5Stone JH Tuckwell K Dimonaco S et al.Trial of tocilizumab in giant-cell arteritis.N Engl J Med. 2017; 377: 317-328Crossref PubMed Scopus (615) Google Scholar The purpose of our retrospective study was to compare outcomes of GCA patients treated with steroids alone versus patients treated with steroids and adjunctive tocilizumab in a single neuro-ophthalmology practice, as well as to compare outcomes from real-world practice with the outcomes reported from the prospectively designed GiACTA. The study protocol was approved by the University of Oklahoma Health Sciences Center Institutional Review Board (IRB) and adhered to the tenets of the Declaration of Helsinki. We identified all biopsy-proven GCA patients managed by a single neuro-ophthalmologist (A.D.P.) from 2005 to 2022 and queried the medical records for cumulative steroid exposure (milligrams of prednisone), including planned taper and escape dosing necessary to maintain disease quiescence, and TCZ use. This provider's practice pattern includes initiating oral prednisone 1 mg/kg per day with tapering by 10 mg/month for steroid-only patients and tapering by 10 mg every 2 weeks for patients approved for concurrent subcutaneous TCZ 162 mg/0.9 mL weekly or biweekly. Length of steroid therapy (in months) required to achieve disease remission (cessation of prednisone or indefinite daily 1 mg dose), disease recurrence, defined by the return of GCA symptoms or new ocular ischemia; adverse events requiring medical intervention; and ocular ischemic complications at presentation (i.e., ischemic optic neuropathy, retinal/ophthalmic artery occlusion, ophthalmoplegia, or transient monocular vision loss) also were recorded. Excluded were patients lost to follow-up prior to 3 months of planned treatment, patients whose steroid dosing was not managed primarily by us, and patients with insufficient documentation. A demographic and clinical summary of the 79 patients meeting study criteria appears in Table 1. Outcome measures of patients treated with steroid therapy alone versus patients treated with steroids and adjunctive TCZ appear in Table 2. There was a statistically significant reduction in mean cumulative steroid dose and length of steroid therapy, and outcomes of the TCZ group were not inferior to those of the steroid-only group regarding disease recurrence and adverse events requiring medical intervention—most frequently, hyperglycemia and infection/sepsis. However, we did not record mild or chronic adverse effects that were more difficult to quantify, such as insomnia, weight gain, fatigue, and quality-of-life indicators.Table 1Demographic and clinical characteristics of the study populationCharacteristicSteroids only (n = 49)Steroids + TCZ (n = 30)p ValueTestAge, mean, (SD; range)76.6 (7.6; 60–95)74.1 (8.8; 58–92)0.094t TestSex Female, % (n)67.3 (33)60.0 (18)0.629Fisher's exact test Male, % (n)32.7 (16)40.0 (12)Ocular manifestations of GCA, % (n)69.4 (34)73.3 (22)0.805Fisher's exact testTCZ, tocilizumab; GCA, giant cell arteritis Open table in a new tab Table 2Comparison of outcome measures of patients treated with steroid therapy alone versus patients treated with steroids and adjunctive TCZCharacteristicSteroids only (n = 49)Steroids + TCZ (n = 30)p ValueTestCumulative steroid exposure, mean mg of prednisone (SD)11,139.5 (6257.5)8263.6 (4263.2)0.015t TestLength of steroid therapy, months (SD)26.5 (31.9)14.8.0 (11.6)0.029t TestDisease recurrence by GCA symptoms or ocular ischemia, % (n)24.5 (12)23.3 (7)0.609Fisher's exact testAdverse events requiring medical intervention, % (n) Any46.9 (23)53.3 (16)0.647Fisher's exact test Sepsis/infection16.3 (8)20.0 (6)Hyperglycemia or diabetic ketoacidosis10.2 (5)20.0 (6)Musculoskeletal (osteoporosis, osteopenia, avascular hip necrosis, spinal compression fracture)4.1 (2)6.7 (2)Uncontrolled hypertension4.1 (2)0Gastrointestinal (melena, ulcer, or perforation)2.0 (1)0Mean follow-up time, months (SD)51.7 (47.4)29.2 (17.9)0.0083t TestTCZ, tocilizumab; GCA, giant cell arteritis Open table in a new tab TCZ, tocilizumab; GCA, giant cell arteritis TCZ, tocilizumab; GCA, giant cell arteritis Notably, TCZ profoundly suppresses C-reactive protein and erythrocyte sedimentation rate independent of disease activity6Unizony S Arias-Urdaneta L Miloslavsky E et al.Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica.Arthritis Care Res (Hoboken). 2012; 64: 1720-1729Crossref PubMed Scopus (236) Google Scholar; therefore, disease recurrence was defined as the return of previously resolved cranial (e.g., jaw claudication, temporal headache, and scalp tenderness) or polymyalgia rheumatica symptoms as opposed to elevation of acute-phase reactants. GiACTA has primarily guided the use of TCZ for GCA, but several criticisms of this study should be considered in real-world practice, as demonstrated by our study. First, GiACTA used much more rapid, unconventional 26- and 52-week steroid tapering protocols (in turn, much lower cumulative steroid exposure) than those commonly encountered in real-world practice. Second, only 0.8% of GiACTA participants had ischemic optic neuropathy (ION)7Tuckwell K Collinson N Dimonaco S et al.Newly diagnosed vs. relapsing giant cell arteritis: baseline data from the GiACTA trial.Semin Arthritis Rheum. 2017; 46: 657-664Crossref PubMed Scopus (46) Google Scholar; 44.3% of our study population presented with ION, and 70.9% presented with ocular ischemia of any kind, suggesting that the GiACTA population was comprised of patients with milder forms of disease. Our study, as well as that of Hayreh et al.,8Hayreh SS Podhajsky PA Raman R Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria.Am J Ophthalmol. 1997; 123: 285-296Abstract Full Text PDF PubMed Google Scholar suggests that patients with severe forms of GCA present to neuro-ophthalmologists, and our study demonstrates that these patients require much higher cumulative steroid exposure than those encountered in GiACTA (nearly a fourfold increase in both steroid-only and TCZ groups). Therefore, adjunctive TCZ should be strongly considered to reduce cumulative steroid exposure in these patients. The authors have no proprietary or commercial interest in any materials discussed in this article. This work was supported by the Eaton Balyeat Resident Research Fund at the University of Oklahoma Health Sciences Center, Dean McGee Eye Institute, Oklahoma City, Okla. We would like to acknowledge the Eaton Balyeat Resident Research Fund at the University of Oklahoma Health Sciences Center, Dean McGee Eye Institute, for supporting our research. 

Anil Patel

Papers

A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder.

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

A comparison of fluorescent and nonfluorescent light sources for phototherapy.

Outcomes of giant cell arteritis patients treated with tocilizumab in a single neuro-ophthalmology practice.