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Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has become increasingly prevalent worldwide. Its core symptoms, including difficulties regulating attention, activity level, and impulses, appear in early childhood and can persist throughout the lifespan. Current pharmacological options targeting catecholamine neurotransmissions have effectively alleviated symptoms in some, but not all affected individuals, leaving clinicians to implement trial-and-error approach to treatment. In this review, we discuss recent experimental evidence from both preclinical and human studies that suggest imbalance of excitation/inhibition (E/I) in the fronto-striatal circuitry during early development may lead to enduring neuroanatomical abnormality of the circuitry, causing persistence of ADHD symptoms in adulthood. We propose a model of precision medicine care that includes E/I balance as a candidate biomarker for ADHD, development of GABA-modulating medications, and use of magnetic resonance spectroscopy and scalp electrophysiology methods to monitor the effects of treatments on shifting E/I balance throughout the lifespan.

Background. Despite widespread use of stimulants to treat ADHD, individual responses vary considerably and few predictors of response have been identified. The identification of reliable and clinically feasible biomarkers would facilitate a precision medicine approach to pharmacological treatment of ADHD. We test the hypothesis that two electroencephalography (EEG) based neural signatures of ADHD, resting aperiodic slope exponent and novelty P3 amplitude, are markers of methylphenidate response in children. We hypothesize that positive response to methylphenidate treatment will be associated with greater abnormality of both neural markers. Methods. Twenty-nine 7-11 year-old children with ADHD and a history of methylphenidate treatment, and 30 controls completed resting EEG and visual oddball event related potential (ERP) paradigms. ADHD participants were characterized as methylphenidate responders (n = 16) or non-responders (n = 13) using the clinical global improvement (CGI-I) scale during blinded retrospective interview. All participants abstained from prescribed medications for at least 48 hours prior to the EEG. Results. As expected, methylphenidate responders (CGI-I rating < 3) demonstrated attenuated P3 amplitude relative to controls. Unexpectedly, methylphenidate non-responders showed atypically flat aperiodic spectral slope relative to controls, while responders did not differ on this measure. Conclusions. ADHD symptoms associated with atypical patterns of intrinsic neural activity may be less responsive to methylphenidate. In contrast, ADHD symptoms associated with abnormal frontal-striatal neural network excitation may be correctable with methylphenidate. Altogether, EEG is a feasible and promising candidate methodology for identifying biomarkers of stimulant response.

Background ADHD commonly co-occurs in children and parents. When ADHD is untreated in parents, it contributes to negative child developmental and treatment outcomes. Screening for parent and child ADHD co-occurrence in pediatric primary care may be an effective strategy for early identification and treatment. There is no data on whether this screening model can be implemented successfully and there exists limited guidance on how to effectively approach parents about their own ADHD in pediatric settings. Even greater sensitivity may be required when engaging with families living in urban, low SES communities due to systemic inequities, mistrust, and stigma. Methods The current pilot study described the first 6 months of implementation of a parent and child ADHD screening protocol in urban pediatric primary care clinics serving a large population of families insured through Medicaid. Parents and children were screened for ADHD symptoms at annual well-child visits in pediatric primary care clinics as part of standard behavioral health screening. Independent stakeholder group meetings were held to gather feedback on factors influencing the implementation of the screening and treatment strategies. Mixed methods were used to examine initial screening completion rates and stakeholder perspectives (i.e., parents, primary care office staff, pediatricians, and behavioral health providers) on challenges of implementing the screening protocol within urban pediatric primary care. Results Screening completion rates were low (19.28%) during the initial 6-month implementation period. Thematic analysis of stakeholder meetings provided elaboration on the low screening completion rates. Identified themes included: 1) divergence between provider enthusiasm and parent hesitation; 2) parent preference versus logistic reality of providers; 3) centering the experiences of people with marginalized identities; and 4) sensitivity when discussing parent mental health and medication. Conclusions Findings highlight the importance of developing flexible approaches to screening parent and child ADHD in urban pediatric health settings and emphasize the importance of cultural sensitivity when working with marginalized and under-resourced families. Trial registration NCT04240756 (27/01/2020).

One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D 4 receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic α 2A -receptor, catechol- O -methyltransferase, D 5 receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa. Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments.

ADHD, sleep, and ADHD treatments are highly interrelated. In this review, we describe the effects of stimulants and non stimulant medications on sleep in children, adolescents, and adults with ADHD. Clinical predictors of sleep problems during pharmacotherapy include age, sleep problems prior to initiating treatment, and dose and dosing schedule. As yet, we have little understanding of the biological or genetic factors related to individual variation in drug response and sleep.

The diagnostic criteria for attention-deficit hyperactivity disorder (ADHD) require both symptoms and impairment to be present. Impairment in functioning is commonly the primary reason for referral, and is also a better predictor of long-term outcomes than ADHD symptoms. And yet, only recently has research begun to examine the impact of ADHD treatments on functional impairment using efficient and psychometrically sound outcome measures. In this article, we identify several noteworthy multidimensional measures of functional impairment (ADHD FX, Barkley Functional Impairment Scale [BFIS], Impairment Rating Scale [IRS], Weiss Functional Impairment Rating Scale [WFIRS]) utilized in recent clinical trials for ADHD, and describe their psychometric properties and clinical utility. We also review existing evidence on the impact of pharmacological and behavioral treatments on different domains of functional impairment in ADHD youth as measured by these specific measures. Further research is needed to evaluate longitudinal effects of ADHD treatments on functional impairment, and the use of these measures in adaptive treatment designs.

In the last 15 years, there has been a marked increase in the number of available stimulant formulations with the emphasis on long-acting formulations, and the introduction of several novel delivery systems such as orally dissolving tablets, chewable tablets, extended-release liquid formulations, transdermal patches, and novel “beaded” technology. All of these formulations involve changes to the pharmaceutical delivery systems of the two existing compounds most commonly employed to treat attention-deficit/hyperactivity disorder (ADHD), amphetamine (AMP) and methylphenidate (MPH). In addition to these new formulations, our knowledge about the individual differences in response has advanced and contributes to a more nuanced approach to treatment. The clinician can now make increasingly informed choices about these formulations and more effectively individualize treatment in a way that had not been possible before. In the absence of reliable biomarkers that can predict individualized response to ADHD treatment, clinical knowledge about differences in MPH and AMP pharmacodynamics, pharmacokinetics, and metabolism can be utilized to personalize treatment and optimize response. Different properties of these new formulations (delivery modality, onset of action, duration of response, safety, and tolerability) will most likely weigh heavily into the clinician's choice of formulation. To manage the broad range of options that are now available, clinicians should familiarize themselves in each of these categories for both stimulant compounds. This review is meant to serve as an update and a guide to newer stimulant formulations and includes a brief review of ADHD and stimulant properties.

Background This study is the first to evaluate an assessment aid for attention‐deficit/hyperactivity disorder (ADHD) according to both Class‐I evidence standards of American Academy of Neurology and De Novo requirements of US Food and Drug Administration. The assessment aid involves a method to integrate an electroencephalographic (EEG) biomarker, theta/beta ratio (TBR), with a clinician's ADHD evaluation. The integration method is intended as a step to help improve certainty with criterion E (i.e., whether symptoms are better explained by another condition). Methods To evaluate the assessment aid, investigators conducted a prospective, triple‐blinded, 13‐site, clinical cohort study. Comprehensive clinical evaluation data were obtained from 275 children and adolescents presenting with attentional and behavioral concerns. A qualified clinician at each site performed differential diagnosis. EEG was collected by separate teams. The reference standard was consensus diagnosis by an independent, multidisciplinary team (psychiatrist, psychologist, and neurodevelopmental pediatrician), which is well‐suited to evaluate criterion E in a complex clinical population. Results Of 209 patients meeting ADHD criteria per a site clinician's judgment, 93 were separately found by the multidisciplinary team to be less likely to meet criterion E, implying possible overdiagnosis by clinicians in 34% of the total clinical sample (93/275). Of those 93, 91% were also identified by EEG, showing a relatively lower TBR (85/93). Further, the integration method was in 97% agreement with the multidisciplinary team in the resolution of a clinician's uncertain cases (35/36). TBR showed statistical power specific to supporting certainty of criterion E per the multidisciplinary team (Cohen's d, 1.53). Patients with relatively lower TBR were more likely to have other conditions that could affect criterion E certainty (10 significant results; P ≤ 0.05). Integration of this information with a clinician's ADHD evaluation could help improve diagnostic accuracy from 61% to 88%. Conclusions The EEG‐based assessment aid may help improve accuracy of ADHD diagnosis by supporting greater criterion E certainty. We proposed and evaluated a method to integrate an electroencephalographic (EEG) biomarker, theta/beta ratio, in series with a clinician's ADHD evaluation. To evaluate, investigators conducted a prospective, triple‐blinded, 13‐site, clinical cohort study. The results support that the EEG integration method may help improve accuracy of ADHD diagnosis by supporting greater criterion E certainty.

Changing practice patterns caused by the pandemic have created an urgent need for guidance in prescribing stimulants using telepsychiatry for attention-deficit hyperactivity disorder (ADHD). A notable spike in the prescribing of stimulants accompanied the suspension of the Ryan Haight Act, allowing the prescribing of stimulants without a face-to-face meeting. Competing forces both for and against prescribing ADHD stimulants by telepsychiatry have emerged, requiring guidelines to balance these factors. On the one hand, factors weighing in favor of increasing the availability of treatment for ADHD via telepsychiatry include enhanced access to care, reduction in the large number of untreated cases, and prevention of the known adverse outcomes of untreated ADHD. On the other hand, factors in favor of limiting telepsychiatry for ADHD include mitigating the possibility of exploiting telepsychiatry for profit or for misuse, abuse, and diversion of stimulants. This Expert Consensus Group has developed numerous specific guidelines and advocates for some flexibility in allowing telepsychiatry evaluations and treatment without an in-person evaluation to continue. These guidelines also recognize the need to give greater scrutiny to certain subpopulations, such as young adults without a prior diagnosis or treatment of ADHD who request immediate-release stimulants, which should increase the suspicion of possible medication diversion, misuse, or abuse. In such cases, nonstimulants, controlled-release stimulants, or psychosocial interventions should be prioritized. We encourage the use of outside informants to support the history, the use of rating scales, and having access to a hybrid model of both in-person and remote treatment.