Rare copy number variants (CNVs) are a key component of the genetic basis of psychiatric conditions, but have not been well characterized for most. We conducted a genome-wide CNV analysis across six diagnostic categories (N = 574,965): autism (ASD), ADHD, bipolar disorder (BD), major depressive disorder (MDD), PTSD, and schizophrenia (SCZ). We identified 35 genome-wide significant associations at 18 loci, including novel associations in SCZ ( SMYD3, USP7 - HAPSTR1 ) and in the combined cross-disorder analysis ( ASTN2 ). Rare CNVs accounted for 1-3% of heritability across diagnoses. In ASD, associations were uniformly positive, consistent with autism having diverse etiologies and clinical presentations. By contrast, CNVs showed a dose-dependent relationship for other diagnoses, including SCZ and PTSD, with reciprocal deletions and duplications having inversely correlated effects and distinct genotype-phenotype relationships. Our findings suggest that genes have effects that are both dose-dependent and pleiotropic, such that a positive influence on one dimension of psychopathology may be accompanied by positive or negative effects on others.

BACKGROUND:Sleep is impaired in children with attention-deficit/hyperactivity disorder (ADHD). However, population-based examination of indicators of sleep insufficiency and bedtime irregularity is limited. This investigation examined associations between ADHD, weeknight sleep insufficiency, and bedtime irregularity in a nationally-representative child sample, and indicators of these sleep outcomes in ADHD. METHODS:Parents of children aged 3-17 years with ADHD (n = 7671) were surveyed through the 2020-2021 National Survey of Children's Health. Inverse probability of treatment weighting generated a weighted matched control sample (n = 51,572). Weighted generalized linear models were performed without and with age-stratification to examine associations between ADHD and sleep, adjusting for sociodemographics in the full sample, and between nineteen sociodemographic and clinical variables and sleep in ADHD. RESULTS:Having ADHD was associated with increased odds of sleep insufficiency and bedtime irregularity relative to controls, even after adjusting for sociodemographic variables. In ADHD, older age was associated with lower sleep insufficiency and greater bedtime irregularity. Black race, increased poverty, higher ADHD severity, depression, and increased screen time were associated with greater sleep insufficiency and bedtime irregularity. Adverse childhood experiences (ACEs) were associated with greater sleep insufficiency. Behavioral/conduct problems, female sex, and absence of both ADHD medication use and ASD diagnosis were associated with poorer bedtime irregularity. Age-stratified results are reported in text. CONCLUSIONS:Children with ADHD face heightened risk for insufficient sleep and irregular bedtimes. Findings suggest intervention targets (e.g., Black race, poverty, depression, screen time) to improve both sleep insufficiency and bedtime irregularity. Results highlight ACEs and behavioral/conduct problems as targets to improve sleep insufficiency and bedtime regularity, respectively. Age-stratified findings are discussed.

Objectives: This review aims to present recent innovations and advancements in attention-deficit/hyperactivity disorder (ADHD) care, encompassing international consensus statement, new medication formulations, digital therapeutics, and neurostimulation devices. Methods: A comprehensive literature search of relevant articles published in the past five years was conducted, emphasizing the evidence base, efficacy, safety, and practical implications of these advancements. Results: The World Federation of ADHD Consensus Statement offers an updated diagnostic and treatment framework rooted in global scientific evidence. There are several newer ADHD medication formulations, including a nonstimulant (Viloxazine extended release) and the first transdermal amphetamine patch approved to treat ADHD. These options offer some unique benefits to personalize treatment based on symptom profile, lifestyle, preferences, and response. Digital tools offer additional means to restructure environments for individuals with ADHD, reducing impairment and reliance on others. In addition, digital therapeutics enhance access, affordability, personalization, and feasibility of ADHD care, complementing or augmenting existing interventions. Trigeminal nerve stimulation emerges as a well-tolerated nonpharmacological, device-based treatment for pediatric ADHD, with initial trials indicating effect sizes comparable to nonstimulant medications. Conclusions: These innovations in ADHD care represent clinically significant new treatment options and opportunities for personalized care. Health care professionals should integrate these developments into clinical practice, mindful of individual patient and family needs and preferences. Future research should assess long-term outcomes, cost-effectiveness, and acceptability of these innovations.

In this chapter, we review scientific findings that form the basis for neuroimaging and neurophysiological biomarkers for ADHD diagnosis and treatment. We then highlight the different challenges in translating mechanistic findings into biomarkers for ADHD diagnosis and treatment. Population heterogeneity is a primary barrier for identifying biomarkers of ADHD diagnosis, which requires shifts toward dimensional approaches that identify clinically useful subgroups or prospective biomarkers that can identify trajectories of illness, function, or treatment response. Methodological limitations, including emphasis on group level analyses of treatment effects in small sample sizes, are the primary barriers to biomarker discovery in ADHD treatment. Modifications to clinical trials, including shifting towards testing biomarkers of a priori prediction of functionally related brain targets, treatment response, and side effects, are suggested. Finally, future directions for biomarker work are discussed.

Background: Executive functioning deficits are central to established neuropsychological models of ADHD. Oscillatory activity, particularly the alpha rhythm (8 -12 Hz) has been associated with cognitive impairments in ADHD. However, most studies to date examined such neural mechanisms underlying executive dysfunction in children and adolescents with ADHD, raising the question of whether and to what extent those ADHD-related working memory impairments are still present in adults. To this end, the current study aimed to investigate the role of alpha event-related decreases (ERD) during working memory processes in adults with and without ADHD. Methods: We collected electroencephalographic (EEG) data from 85 adults with a lifetime diagnosis of ADHD and 105 controls (aged 32 -64), while they performed a continuous performance (CPT) and a spatial delayed response working memory task (SDRT). Time-frequency and independent component analysis (ICA) was used to identify alpha (8 -12 Hz) clusters to examine group and condition effects during the temporal profile of sustained attention and working memory processes (encoding, maintenance, retrieval), loads (low and high) and trial type (go and nogo). Results: Individuals with ADHD exhibited higher reaction time-variability in SDRT, and slower response times in SDRT and CPT, despite no differences in task accuracy. Although working memory load was associated with stronger alpha ERD in both tasks and both groups (ADHD, controls), we found no consistent evidence for attenuated alpha ERD in adults with ADHD, failing to replicate effects reported in children. In contrast, when looking at the whole sample, the correlations of alpha power during encoding with inattention and hyperactivity-impulsivity symptoms were significant, replicating prior findings in children with ADHD, but suggesting an alternate source for these effects in adults. Conclusions: Our results corroborate the robustness of alpha as a marker of visual attention and suggest that occipital alpha ERD normalizes in adulthood, but with unique contributions of centro-occipital alpha ERD, suggesting a secondary source. This implies that deviations in processes other than previously reported visuospatial cortex engagement may account for the persistent symptoms and cognitive deficits in adults with a history of ADHD.

Moderated nonlinear factor analysis (MNLFA) has emerged as an important and flexible data analysis tool, particularly in integrative data analysis setting and psychometric studies of measurement invariance and differential item functioning. Substantive applications abound in the literature and span a broad range of disciplines. MNLFA unifies item response theory, multiple group, and multiple indicator multiple cause modeling traditions, and it extends these frameworks by conceptualizing latent variable heterogeneity as a source of differential item functioning. The purpose of this article was to illustrate a flexible Markov chain Monte Carlo-based approach to MNLFA that offers statistical and practical enhancements to likelihood-based estimation while remaining plug and play with established analytic practices. Among other things, these enhancements include (a) missing data handling functionality for incomplete moderators, (b) multiply imputed factor score estimates that integrate into existing multiple imputation inferential methods, (c) support for common data types, including normal/continuous, nonnormal/continuous, binary, ordinal, multicategorical nominal, count, and two-part constructions for floor and ceiling effects, (d) novel residual diagnostics for identifying potential sources of differential item function, (e) manifest-by-latent variable interaction effects that replace complex moderation function constraints, and (f) integration with familiar regression modeling strategies, including graphical diagnostics. A real data analysis example using the Blimp software application illustrates these features.

Objective: ADHD is a prevalent neurodevelopmental disorder characterized by symptoms of inattention and hyperactivity-impulsivity. Impairments in executive functioning (EF) are central to models of ADHD, while alpha-band spectral power event-related decreases (ERD) have emerged as a putative electroencephalography (EEG) biomarker of EF in ADHD. Little is known about the roles of EF and alpha ERD and their interactions with symptoms of ADHD. Method: We estimated network models of ADHD symptoms and integrated alpha ERD measures into the symptom network. Results: EF emerges as a bridge network node connecting alpha ERD and the hyperactivity/impulsivity and inattention symptoms. We found that EF most closely relates to a subset of symptoms, namely the motoric symptoms, “seat” (difficulty staying seated), and “runs” (running or climbing excessively). Conclusions: EF functions as a bridge node connecting alpha ERD and the ADHD symptom network. Motoric-type symptoms and EF deficits may constitute important nodes in the interplay between behavior/symptoms, cognition, and neurophysiological markers of ADHD.

Objective: The combination of d-methylphenidate and guanfacine (an a-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.Method: A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity. Results: Higher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R2= 0.34-0.41) as clinical measures alone (R2 = 0.14-.21).Conclusion: We identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD. Clinical trial registration information: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; NCT00429273

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and persistent tic disorder (PTD) are two neurodevelopmental disorders that frequently co-occur. Contributions of each disorder to cognitive and behavioral deficits have been reported. In this paper, we tested 3 models of pathophysiology for the two disorders (additive, interactive, and phenotypic) using resting-state connectivity associated with each disorder separately and together. METHODS: Participants were 148 children (55 with ADHD only, 33 with ADHD and PTD, 27 with PTD only, and 33 healthy control subjects) at ages 8 to 12 years. Following diagnostic interviews and behavioral assessment, participants underwent a 128-channel electroencephalography recording. Resting-state, cortical source-level effective connectivity was analyzed across the 4 groups using a 2 3 2 factorial design with factors of ADHD (with/without) RESULTS: ADHD diagnosis was the primary driver of cognitive and behavioral deficits, while deficits associated with PTD were primarily with thought problems and internalizing problems when compared with controls. Subadditive effects were observed in co-occurring ADHD1PTD for parent-rated behavioral problems and cognitive functions. Aberrant effective connectivity was primarily associated with ADHD, more specifically with lower posterior and occipital-frontal connectivity, while children with PTD exhibited greater left postcentral to precuneus connectivity. Weaker ADHD-related connectivity was associated with more severe behavioral problems, including internalizing behaviors, thought problems, and working memory deficits. CONCLUSIONS: Similar to general behavioral deficits, aberrant resting-state neural connectivity in pediatric ADHD and PTD combines additively in co-occurring cases. The findings of this study support ADHD as a focus of treatment in comorbid cases, given the driving role of ADHD in both behavioral and neurophysiological deficits.

In 2019, trigeminal nerve stimulation (TNS) became the first FDA-cleared, nonpharmacological, device-based monotherapy for treatment of ADHD in children ages 7 to 12 years. TNS is safe and effective at reducing core symptoms of ADHD in approximately 50% of children. However, clinical acceptance and use of the treatment has been slow, partially due to lack of familiarity with how to use the device clinically. This presentation will give detailed instructions and insights to clinicians who would like to utilize TNS as a treatment for ADHD.

Emotional dysregulation and lability are commonly associated features in ADHD, that are often not well-addressed by existing therapies. External trigeminal nerve stimulation (TNS) is a noninvasive method of brain modulation that received FDA device clearance in 2019 for the treatment of children with ADHD between 7 and 12 years old. Children randomized to active TNS exhibited a ∼50% response rate and significantly greater improvements in ADHD symptoms (p < .005) relative to children in the sham condition. TNS treatment responders, defined using the Clinical Global Impressions Scale of Improvement (CGI-I) less than or equal to 2, additionally exhibited improved executive functions. This presentation will address whether TNS active treatment and/or those with positive treatment response show improvements on secondary outcomes such as emotional regulation and control among children with ADHD. Sixty-two children aged 8 to 12 years with K-SADS–diagnosed ADHD were randomly assigned to 4 weeks of nightly active or sham TNS treatment. Children randomized to the sham condition were allowed to cross over into open-label active treatment. Behavioral measures of emotional control, emotional lability, irritability, and depressive symptomatology were examined according to treatment assignment as well as by responder status. ANOVAs were used to examine pretreatment differences between treatment groups as well as responders and nonresponders, and repeated-measures ANOVAs were used to test the TNS-related change in emotional functioning. No significant differences between the active and sham groups emerged on the measures of emotional control and regulation. TNS responders had significantly better emotional control and less emotional lability prior to treatment (p’s < .05). A significant responder x time interaction effect (p < .05), however, indicated that responders also exhibited greater TNS-related improvement in emotional functioning after treatment compared to nonresponders. TNS responders exhibited less emotional dysregulation at baseline compared to nonresponders but also exhibited greater improvements in emotion regulation in addition to reduced levels of core ADHD symptoms. TNS treatment can result in better cognitive and emotional control in ADHD.

ObjectiveThe combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.MethodA total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.ResultsCombined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.ConclusionThese findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.Diversity & Inclusion StatementWe worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.

BACKGROUND:Attention-deficit/hyperactivity disorder is characterized by neurobiological heterogeneity, possibly explaining why not all patients benefit from a given treatment. As a means to select the right treatment (stratification), biomarkers may aid in personalizing treatment prescription, thereby increasing remission rates.METHODS:The biomarker in this study was developed in a heterogeneous clinical sample (N = 4249) and first applied to two large transfer datasets, a priori stratifying young males (<18 years) with a higher individual alpha peak frequency (iAPF) to methylphenidate (N = 336) and those with a lower iAPF to multimodal neurofeedback complemented with sleep coaching (N = 136). Blinded, out-of-sample validations were conducted in two independent samples. In addition, the association between iAPF and response to guanfacine and atomoxetine was explored.RESULTS:Retrospective stratification in the transfer datasets resulted in a predicted gain in normalized remission of 17% to 30%. Blinded out-of-sample validations for methylphenidate (n = 41) and multimodal neurofeedback (n = 71) corroborated these findings, yielding a predicted gain in stratified normalized remission of 36% and 29%, respectively.CONCLUSIONS:This study introduces a clinically interpretable and actionable biomarker based on the iAPF assessed during resting-state electroencephalography. Our findings suggest that acknowledging neurobiological heterogeneity can inform stratification of patients to their individual best treatment and enhance remission rates.

Attention-deficit hyperactivity disorder (ADHD) is a debilitating disorder with apparent roots in abnormal brain development. Here, we quantified the level of individual brain maturation in children with ADHD using structural neuroimaging and a recently developed machine learning algorithm. More specifically, we compared the BrainAGE index between three groups matched for chronological age (mean ± SD: 11.86 ± 3.25 years): 89 children diagnosed with ADHD, 34 asymptomatic siblings of those children with ADHD, and 21 unrelated healthy control children. Brains of children with ADHD were estimated significantly younger (−0.85 years) than brains of healthy controls (Cohen’s d = −0.33; p = 0.028, one-tailed), while there were no significant differences between unaffected siblings and healthy controls. In addition, more severe ADHD symptoms were significantly associated with younger appearing brains. Altogether, these results are in line with the proposed delay of individual brain maturation in children with ADHD. However, given the relatively small sample size (N = 144), the findings should be considered preliminary and need to be confirmed in future studies.

ObjectivesExternal trigeminal nerve stimulation (TNS) is a noninvasive method of brain modulation that received FDA device clearance in 2019 for treatment of children aged 7 to 12 years with ADHD. Children randomized to active TNS exhibited significantly greater improvements in ADHD symptoms (p < .005) than sham and increased EEG power in the right frontal (F4) and frontal midline (Fz) brain regions. This presentation examines changes in resting-state functional connectivity to more fully characterize the neural mechanisms underlying TNS treatment–related improvements in ADHD.MethodsSixty-two children aged 8 to 12 years with K-SADS–diagnosed ADHD were randomly assigned to 4 weeks of nightly active or sham TNS treatment. The primary outcomes were the clinician-rated ADHD Rating Scale (ADHD-RS) and the Clinical Global Impression (CGI) scales. The secondary outcomes included cognitive measures, weekly ratings of behavioral executive functions (Behavior Rating Inventory of Executive Function [BRIEF]), and EEG measures at pretreatment and posttreatment. Cortical source–level resting-state functional connectivity was estimated from 128-channel EEGs using the groupSIFT program within the EEGLAB data analysis platform.ResultsAfter 4 weeks of treatment, the active TNS group exhibited stronger connectivity between the anterior and posterior nodes of the default mode network (DMN) and lower connectivity between the frontal and medial nodes of the salience and executive control networks than the sham group (p's range = .004-.008). Lower connectivity among edges involving the right frontal nodes (right insula, right lateral prefrontal cortex) were significantly associated with improved ADHD symptomatology (r's range = .29-.35; p = .02-.05) at the end of treatment. TNS responders trended toward stronger connectivity within the DMN (p = .06), which correlated with greater improvement in ADHD symptoms (r = .33; p = .03) and better parent-rated executive function (BRIEF working memory [WM] r = -.30; p = .05).ConclusionsThe neural mechanisms underlying the TNS treatment effects in ADHD involve normalization of connectivity within several resting-state networks (DMN, salience, executive control), particularly those involving mid- and right-frontal connections.ADHD, NM, TREAT ObjectivesExternal trigeminal nerve stimulation (TNS) is a noninvasive method of brain modulation that received FDA device clearance in 2019 for treatment of children aged 7 to 12 years with ADHD. Children randomized to active TNS exhibited significantly greater improvements in ADHD symptoms (p < .005) than sham and increased EEG power in the right frontal (F4) and frontal midline (Fz) brain regions. This presentation examines changes in resting-state functional connectivity to more fully characterize the neural mechanisms underlying TNS treatment–related improvements in ADHD. External trigeminal nerve stimulation (TNS) is a noninvasive method of brain modulation that received FDA device clearance in 2019 for treatment of children aged 7 to 12 years with ADHD. Children randomized to active TNS exhibited significantly greater improvements in ADHD symptoms (p < .005) than sham and increased EEG power in the right frontal (F4) and frontal midline (Fz) brain regions. This presentation examines changes in resting-state functional connectivity to more fully characterize the neural mechanisms underlying TNS treatment–related improvements in ADHD. MethodsSixty-two children aged 8 to 12 years with K-SADS–diagnosed ADHD were randomly assigned to 4 weeks of nightly active or sham TNS treatment. The primary outcomes were the clinician-rated ADHD Rating Scale (ADHD-RS) and the Clinical Global Impression (CGI) scales. The secondary outcomes included cognitive measures, weekly ratings of behavioral executive functions (Behavior Rating Inventory of Executive Function [BRIEF]), and EEG measures at pretreatment and posttreatment. Cortical source–level resting-state functional connectivity was estimated from 128-channel EEGs using the groupSIFT program within the EEGLAB data analysis platform. Sixty-two children aged 8 to 12 years with K-SADS–diagnosed ADHD were randomly assigned to 4 weeks of nightly active or sham TNS treatment. The primary outcomes were the clinician-rated ADHD Rating Scale (ADHD-RS) and the Clinical Global Impression (CGI) scales. The secondary outcomes included cognitive measures, weekly ratings of behavioral executive functions (Behavior Rating Inventory of Executive Function [BRIEF]), and EEG measures at pretreatment and posttreatment. Cortical source–level resting-state functional connectivity was estimated from 128-channel EEGs using the groupSIFT program within the EEGLAB data analysis platform. ResultsAfter 4 weeks of treatment, the active TNS group exhibited stronger connectivity between the anterior and posterior nodes of the default mode network (DMN) and lower connectivity between the frontal and medial nodes of the salience and executive control networks than the sham group (p's range = .004-.008). Lower connectivity among edges involving the right frontal nodes (right insula, right lateral prefrontal cortex) were significantly associated with improved ADHD symptomatology (r's range = .29-.35; p = .02-.05) at the end of treatment. TNS responders trended toward stronger connectivity within the DMN (p = .06), which correlated with greater improvement in ADHD symptoms (r = .33; p = .03) and better parent-rated executive function (BRIEF working memory [WM] r = -.30; p = .05). After 4 weeks of treatment, the active TNS group exhibited stronger connectivity between the anterior and posterior nodes of the default mode network (DMN) and lower connectivity between the frontal and medial nodes of the salience and executive control networks than the sham group (p's range = .004-.008). Lower connectivity among edges involving the right frontal nodes (right insula, right lateral prefrontal cortex) were significantly associated with improved ADHD symptomatology (r's range = .29-.35; p = .02-.05) at the end of treatment. TNS responders trended toward stronger connectivity within the DMN (p = .06), which correlated with greater improvement in ADHD symptoms (r = .33; p = .03) and better parent-rated executive function (BRIEF working memory [WM] r = -.30; p = .05). ConclusionsThe neural mechanisms underlying the TNS treatment effects in ADHD involve normalization of connectivity within several resting-state networks (DMN, salience, executive control), particularly those involving mid- and right-frontal connections.ADHD, NM, TREAT The neural mechanisms underlying the TNS treatment effects in ADHD involve normalization of connectivity within several resting-state networks (DMN, salience, executive control), particularly those involving mid- and right-frontal connections.

The development of treatment biomarkers for psychiatric disorders has been challenging, particularly for heterogeneous neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD). Promising findings are also rarely translated into clinical practice, especially with regard to treatment decisions and development of novel treatments. Despite this slow progress, the available neuroimaging, electrophysiological (EEG) and genetic literature provides a solid foundation for biomarker discovery. This article gives an updated review of promising treatment biomarkers for ADHD which may enhance personalized medicine and novel treatment development. The available literature points to promising pre-treatment profiles predicting efficacy of various pharmacological and non-pharmacological treatments for ADHD. These candidate predictive biomarkers, particularly those based on low-cost and non-invasive EEG assessments, show promise for the future stratification of patients to specific treatments. Studies with repeated biomarker assessments further show that different treatments produce distinct changes in brain profiles, which track treatment-related clinical improvements. These candidate monitoring/response biomarkers may aid future monitoring of treatment effects and point to mechanistic targets for novel treatments, such as neurotherapies. Nevertheless, existing research does not support any immediate clinical applications of treatment biomarkers for ADHD. Key barriers are the paucity of replications and external validations, the use of small and homogeneous samples of predominantly White children, and practical limitations, including the cost and technical requirements of biomarker assessments and their unknown feasibility and acceptability for people with ADHD. We conclude with a discussion of future directions and methodological changes to promote clinical translation and enhance personalized treatment decisions for diverse groups of individuals with ADHD.

AbstractBackgroundA recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).MethodsThe discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8–40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.ResultsWhen combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).ConclusionsWe detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.