Transcranial direct current stimulation (tDCS) is a possible alternative to psychostimulants in Attention-Deficit/Hyperactivity Disorder (ADHD), but its mechanisms of action in children and adolescents with ADHD are poorly understood. We conducted the first 15-session, sham-controlled study of anodal tDCS over right inferior frontal cortex (rIFC) combined with cognitive training (CT) in 50 children/adolescents with ADHD. We investigated the mechanisms of action on resting and Go/No-Go Task-based QEEG measures in a subgroup of 23 participants with ADHD . We failed to find a significant sham versus anodal tDCS group differences in QEEG spectral power during rest and Go/No-Go Task performance, a correlation between QEEG and Go/No-Go Task performance, and changes in clinical and cognitive measures. These findings extend the non-significant clinical and cognitive effects in our sample of 50 children/adolescents with ADHD. Given that the subgroup of 23 participants would have been underpowered, the interpretation of our findings is limited and should be used as a foundation for future investigations. Larger, adequately powered randomized controlled trials should explore different protocols titrated to the individual and using comprehensive measures to assess cognitive, clinical, and neural effects of tDCS and its underlying mechanisms of action in ADHD. •The mechanism of action of tDCS in ADHD are poorly understood.•We combined 15-session anodal tDCS over the rIFC with cognitive training in ADHD children.•EEG was measured at rest and during a cognitive control task.•Real vs sham tDCS showed no significant effect on EEG at rest or during Go/No-Go task.•Real versus sham tDCS showed no significant cognitive or symptom improvements. ADHD isThe gold-standard treatment for ADHD are psychostimulants, which improve ADHD symptoms in roughly 70% of individuals with ADHD. However, psychostimulants have been associated with side-effects , poor adA promising neurotherapeutic alternative is transcranial direct current stimulation (tDCS), which can potentially modulate key dysfunctional brain regions associated with ADHD with longer-term neuroplastic effects that drugs cannot offer . TDCS inSystematic reviews and meta-analyses of tDCS studies in ADHD suggest limited evidence of clinical or cognitive improvement with tDCS . HoweverHardly anything is known about the neurophysiological substrates of tDCS effects in ADHD, with only three studies investigating these. In a double-blind, crossover RCT study with 10 adolescents with ADHD, single-session conventional anodal tDCS, anodal High Definition (HD)-tDCS or sham tDCS over rIFC led to enhanced N2 and P3 amplitude during an n-back WM task compared to sham . In a doCompared to event-related potentials (ERPs), EEG spectral power has been a preferred measure of treatment/stimulation response in both clinical and non-clinical studies. Findings in healthy adults on the effects of tDCS on spectral power are mixed. In one RCT, single-session anodal tDCS over the rIFC led to a reduction in absolute theta power at rest and improved inhibitory performance compared to sham , suggestTo our knowledge, this is the first study to examine the neuromodulatory effects of multi-session anodal tDCS combined with cognitive training over the rIFC on EEG spectral power in children and adolescents with ADHD. Based on aforementioned findings in healthy adults, we hypothesized that 15 sessions of anodal versus sham tDCS over the rIFC combined with multi-EF training would lead to a decrease during rest and an increase during task performance in absolute theta power. We also hypothesized that this effect would be associated with improved performance during a motor response inhibition Go/No-Go task.22.1In a double-blind, sham-controlled, parallel RCT (ISRCTN: 48265228), 50 boys with ADHD received 15 sessions of anodal or sham tDCS over the rIFC combined with multi-EF training over 3 weeks . We meas2.2For the purposes of this paper, only participants that completed baseline and post-treatment EEG recordings were included. This is because, of the 50 participants, 21 had no EEG data recorded at all, while only 16 participants had EEG data recorded at the 6-month follow-up, which was too few for data analysis. Thus, this left 13 participants in the anodal and 16 in the sham tDCS group with baseline and post-treatment EEG eligible for data analysis.Twenty-nine male participants (10- to 18-years) had a clinical DSM-5 diagnosis of ADHD assessed by an experienced child psychiatrist and confirmed using the Schedule of Affective Disorders and Schizophrenia for School‐Age Children‐Present and Lifetime version (K‐SADS‐PL). ParticiBaseline assessment was scheduled at least two weeks after medication titration. Eighteen participants received stable ADHD medications . To minimize the risk that psychostimulants might mask the effect of stimulation, participants on psychostimulants were asked to abstain for at least 24 h before each assessment session. Of the 12 participants who abstained, 5 chose to abstain throughout the trial period (>24 h before baseline until after post-assessment), while 7 abstained 24 h before each the baseline and post-assessment only see .Table 1B2.32.3.1The adult version of the Maudsley Attention and Response Suppression (MARS) Task battery  was used2.3.2Treatment effects in ADHD symptoms was measured with the caregiver-rated ADHD Rating Scale–IV (ADHD-RS) Home Version  and Conn2.3.3Safety was measured with caregiver-rated side effects  and adve2.4Participants performed one block of the adult variant of the Maudsley Attention and Response Suppression (MARS) Go/No-Go Task, a measure of motor response inhibition . In 73.42.5EEG was recorded from an 8-channel DC-coupled recording system using a wearable headset, manufactured by gtec . Active dry electrodes (Sahara) with gold-plated pins and pre-amplification module were attached to the cap system, which allowed recordings using the 10–20 montage. The EEG data was wirelessly (using Bluetooth) transmitted to the recording laptop.2.6During all recordings, the pre-amplification module in the active electrodes allows to keep the signal stable (~20 µV) and the impedances below (30 kΩ). Adhesive ground and reference electrodes were positioned at the mastoids. The signal was digitized at a sampling rate of 500 Hz, with additional online filters .Participants were seated on a height adjustable chair in a testing lab. Stimuli were presented on a laptop at a distance of approximately 30 cm.2.7Analyses were carried out in the open-source EEGLAB software. Researc2.82/Hz) within each frequency band was computed for each electrode individually separately for the task and the rest periods as well as averaged across all electrode sites  to reduce the number of comparisons. Due to the main focus being on the electrode over the stimulation site (F8), analyses of the other electrodes are reported in the Quantitative EEG was investigated for resting state and EEG-Go/No-Go Task. Data were segmented into 2 s epochs and power spectra were computed using a fast Fourier transform with a 10% Hanning window. Analyses focused on alpha (8–14 Hz), theta (3–7 Hz) and beta (15–30 Hz) band differences between two groups . EEG absolute power density  with Group  as a between-subjects factor and Time (baseline vs post-treatment) as a within-subjects factor, while covarying for baseline age in months and ADHD-RS scores. The covariates were selected to adjust for baseline differences, with the anodal tDCS group being significantly younger and reported higher ADHD-RS Total Score see .p-values less than 0.1, which was applied separately to the different frequency bands, secondary clinical outcomes, and secondary cognitive outcomes. We did not correct for multiple testing on Offline Go/No-Go, or ADHD -RS as these were considered primary outcome measures . Analyses were conducted with IBM SPSS Statistics 26 .The alpha level was set at 0.05. To correct for multiple testing, False Discovery Rate (FDR) correction with Benjamini-Hochberg  was applsee also ). In the2.10This trial received local research ethics committee approval (REC ID: 17/LO/0983) and was conducted in accordance with the Declaration of Helsinki .3Out of the 29 individuals, 6 individuals were excluded from all analyses due to extreme values driven by large EEG artifacts. Only 23 recordings were available for the analysis .3.1Compared to sham, the anodal tDCS group was on average 2-years younger, had higher ADHD-RS Total & Inattentive Scores and Conners’ 3-P DSM-Inattentive Scores, and fewer years in education. Cognitively, the anodal compared to the sham tDCS group showed significantly poorer performance on the following offline tasks: Go/No-Go (PI%), Simon (Simon RT Effect), Macworth Clock (Omissions & Commissions), and NIH WM Tasks  see .3.23.2.1There was no significant Group-by-Time interaction and no significant main effects of Group or Time on EEG activity  during rest based on the average of all electrodes or at F8 only .Table 2S3.2.2Based on the average across all electrodes, there was no significant Group-by-Time interaction effect and no significant main effect of Group on EEG activity during Go/No-Go Task performance. There was a main effect of Time on theta and alpha activity, with lower theta and alpha activity at post-treatment compared to baseline, but this effect did not survive FDR correction . There wBased on F8 only, there was no significant Group-by-Time interaction effect and no significant main effect of group on EEG activity . There was a significant main effect of Time, showing lower alpha, beta and theta activity at post-treatment compared to baseline, but this was no longer significant after FDR correction. There was also a significant time-by-age interaction effect  = 9.91,unadjusted p = 0.006, FDR adjusted p = 0.10; alpha, F = 6.39,unadjusted p = 0.021, FDR adjusted p = 0.31; beta  = 5.86, unadjusted p = 0.026, FDR adjusted p = 0.31), showing higher theta and alpha activity in younger subjects at pre- compared to post-treatment, which was no longer significant after FDR correction .3.3p = 0.01).There was no significant main effects of Group, Time, or Group-by-Time interaction effect that survived FDR Correction on clinical or offline cognitive measures , except 4This is the first double-blind, sham-controlled RCT to test the neurofunctional mechanisms of action of multi-session, anodal tDCS over the rIFC combined with cognitive training in children and adolescents with ADHD on QEEG spectral power. There were no significant differences between sham and anodal tDCS on QEEG spectral power during rest and Go/No-Go Task performance. Further, both sham and real tDCS showed lower EEG spectral power at post-treatment compared to baseline, although this did not survive FDR correction for multiple comparisons. Finally, there were no statistical differences in these subgroups in clinical and cognitive outcome measures. These null findings in QEEG spectral power, and the pattern of results in clinical and cognitive outcomes in this subgroup of 23 children and adolescents with ADHD extends the evidence of overall null findings in clinical or cognitive outcomes following anodal tDCS over the rIFC relative to sham in the original sample of 50 children and adolescents with ADHD published previously . The lacThe lack of a significant tDCS effect on QEEG measures contrasts with previous evidence of reduced absolute theta power during rest after a single session of anodal compared to sham tDCS over the rIFC in adults without ADHD . AnotherThese findings might suggest that multi-session tDCS over rIFC combined with CT had no effect on EEG measures of spectral power during rest or task performance in children with ADHD. However, this lack of effect on EEG spectral power could be related to the underpowered sample size (n = 23) and/or baseline differences, with the anodal tDCS group being younger and having higher parent ratings on ADHD-RS and Conners’ 3-P compared to sham. A potential confounding effect of age chimes with previous evidence indicating that QEEG varies as a function of age . ChildreBoth groups showed improvement in EEG Go/No-Go PI and offline WCST Perseverative Errors from baseline to post-treatment. A similar effect of time effect was observed in the larger sample of 50 ADHD children for cognitive performance on an offline Go/No-Go and other offline tasks measuring ADHD-related EF . HoweverGiven the insufficient EEG data at the 6-month follow-up assessment, we could not test for potential longer-term tDCS effects on EEG measures after a period of consolidation . However4.1d > 1.00), which could be related to the statistical null findings. These findings should therefore be replicated using adequately powered sample sizes. The attrition rate of this study was very high (42%) compared to studies using QEEG in children above the age of 4 either with and without ADHD (5%−25%)(Although this RCT had a relatively larger sample (n = 50) than other tDCS studies in children and adolescents with ADHD, EEG data could only be collected for 29 participants at post-treatment , and there was insufficient EEG data at follow-up (n = 16) to test longer-term effects of tDCS. Thus, this sample of 23 participants is only sufficiently powered to detect exceptionally larger effects , which i (5%−25%) that wer (5%−25%), as evid4.2This study in 23 children with ADHD failed to show a differential effect of 15 sessions of anodal versus sham tDCS & CT on EEG spectral power, and cognitive or clinical outcomes. The findings extend our previous findings in a larger group of 50 ADHD children of no superior effects of anodal versus sham tDCS & CT on clinical or cognitive measures by showing no underlying neurofunctional mechanism of action in a subgroup . Althoug10.13039/501100000317Action Medical Research (GN2426), the 10.13039/100013999Garfield Weston Foundation, and 10.13039/501100000272National Institute for Health Research (NIHR) Biomedical Research Center at South London and the Maudsley NHS Foundation Trust, and 10.13039/501100000764King's College London to KR. KR has received additional research support for other projects from the 10.13039/501100000265Medical Research Council (MR/P012647/1), and the National Institute for Health Research (NIHR) Biomedical Research Center at South London and the Maudsley NHS Foundation Trust, and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funders were not involved in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.This work was supported by grants from Contributions according to Contributor Roles Taxonomy (CRediT) (casrai.org/credit/). Conceptualization. Katya Rubia, Roi Cohen-Kadosh, Samuel J. Westwood, Natali. Bozhilova, Marion Criaud, Sheut-Ling Lam, Steve Lukito, Bruce Wexler, Philip Asherson. Data curation. Samuel J. Westwood, Natali Bozhilova, Marion Criaud, Sheut-Ling Lam, Steve Lukito, Sophie Wallace-Hanlon and Afroditi Kostara. Formal analysis. Samuel J. Westwood, Natali Bozhilova, Roi Cohen-Kadosh, and Katya Rubia, Funding acquisition. Katya Rubia, Bruce Wexler, Roi Cohen-Kadosh, Philip Asherson. Investigation, Samuel J. Westwood, Marion Criaud, Sheut-Ling Lam, Steve Lukito, Sophie Wallace-Hanlon, Olivia S. Kowalczyk, Afroditi Kostara and Joseph Mathew. Methodology. Katya Rubia, Roi Cohen-Kadosh, Bruce Wexler, Samuel J. Westwood, Marion Criaud, Sheut-Ling Lam, Steve Lukito, Olivia S. Kowalczyk, Philip Asherson. Project administration. Samuel J. Westwood and Katya Rubia. Resources. Katya Rubia, Bruce Wexler, Roi Cohen-Kadosh, Philip Asherson. Software. Bruce Wexler, Katya Rubia, Marion Criaud,. Supervision. Samuel J. Westwood and Katya Rubia. Validation. Samuel J. Westwood and Katya Rubia. Visualization. Natali Bozhilova. Writing – original draft preparation. Samuel J. Westwood, Natali Bozhilova, and Katya Rubia. Writing – review and editing. Samuel J. Westwood, Natali Bozhilova, Katya Rubia, Marion Criaud, Sheut-Ling Lam, Steve. Lukito, Sophie Wallace-Hanlon, Olivia S. Kowalczyk, Bruce Wexler, Roi Cohen-Kadosh.The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. This trial received research ethics committee approval from The NHS Research Authority, London Camberwell St Giles Research Ethics Committee (REC ID: 17/LO/0983) in November 2017.Informed consent was obtained from all participants involved in the study.BEW is Chief Scientist and an equity holder in the Yale Start Up company C8 Sciences that sells the cognitive training program evaluated in this study. RCK serves on the scientific advisory boards for Neuroelectrics and Innosphere. PA reports honoraria for consultancy to Shire/Takeda, Eli Lilly and Novartis; educational and research awards from Shire, Lilly, Novartis, Vifor Pharma, GW Pharma and QbTech; and speaking at sponsored events for Shire, Lilly, Flynn Pharma and Novartis. KR has received funding from Takeda pharmaceuticals for another project and consultancy fees from Lundbeck and Supernus which were paid into King’s College London and used for research.


ADHD in adults is a common and debilitating neurodevelopmental mental health condition. Yet, diagnosis, clinical management and monitoring are frequently constrained by scarce resources, low capacity in specialist services and limited awareness or training in both primary and secondary care. As a result, many people with ADHD experience serious barriers in accessing the care they need.Professionals across primary, secondary, and tertiary care met to discuss adult ADHD clinical care in the United Kingdom. Discussions identified constraints in service provision, and service delivery models with potential to improve healthcare access and delivery. The group aimed to provide a roadmap for improving access to ADHD treatment, identifying avenues for improving provision under current constraints, and innovating provision in the longer-term. National Institute for Health and Care Excellence (NICE) guidelines were used as a benchmark in discussions.The group identified three interrelated constraints. First, inconsistent interpretation of what constitutes a ‘specialist’ in the context of delivering ADHD care. Second, restriction of service delivery to limited capacity secondary or tertiary care services. Third, financial limitations or conflicts which reduce capacity and render transfer of care between healthcare sectors difficult. The group recommended the development of ADHD specialism within primary care, along with the transfer of routine and straightforward treatment monitoring to primary care services. Longer term, ADHD care pathways should be brought into line with those for other common mental health disorders, including treatment initiation by appropriately qualified clinicians in primary care, and referral to secondary mental health or tertiary services for more complex cases. Long-term plans in the NHS for more joined up and flexible provision, using a primary care network approach, could invest in developing shared ADHD specialist resources.The relegation of adult ADHD diagnosis, treatment and monitoring to specialist tertiary and secondary services is at odds with its high prevalence and chronic course. To enable the cost-effective and at-scale access to ADHD treatment that is needed, general adult mental health and primary care must be empowered to play a key role in the delivery of quality services for adults with ADHD. ADHD is a neurodevelopmental disorder that develops during childhood or early adolescence and frequently persists into adulthood, where it is then referred to as adult ADHD. The disorder is defined by a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with or reduces the quality of functioning in daily life . ADHD fiFollow-up studies of children with ADHD show that symptoms and impairment frequently persist into adulthood. An initial review of follow-up studies, mainly from the United States, estimated that 15% of children with ADHD retained the full diagnosis by the age of 25 years . FurtherAdverse outcomes of ADHD are well-documented and often severe. These include social and relationship problems , delinquThe benefits of treatment are well documented and can reduce both immediate and long-term risks and adverse outcomes , 30. DelNational and consensus guidelines for the treatment of ADHD in adults are similar across the world –46, inclLike other guidelines for adult ADHD in European countries and worldwide, NICE recommend that diagnostic assessments should be conducted by adult mental health care professionals with training in diagnosis and treatment of ADHD. Thus, NICE guidelines recommend a higher standard of expertise for assessment and treatment than for other common mental health disorders such as anxiety and depression, which are frequently managed solely by non-specialists within primary care. In the UK and elsewhere, ADHD is mainly managed by tertiary and some secondary mental health services with relevant expertise. Whilst such specialization ensures appropriate targeting of treatments for adult ADHD, over-specialization runs the risk of limiting access to diagnostic assessments and treatment.Treatment rates for ADHD are far lower than expected. Raman et al. (2018) used population-based databases from 13 countries between 2001 and 2015, and applied a common approach to define study populations and parameters across countries . Rates oIn the context of guidance from NICE , evidencHowever, ADHD is not always so complex or severe that it meets the requirements for involvement of secondary or tertiary care mental health services. Integration of ADHD services into more generalist clinical services could therefore also occur, within clear parameters, at the level of primary care, following treatment models for other common mental health problems such as anxiety disorders and depression. It is in this context that we set out to consider the potential role of primary care services in the diagnosis and management of adult ADHD and examine new models of care that have developed in recent years. To achieve this, we brought together healthcare professionals from primary, secondary and tertiary care services in the UK to identify bottlenecks in service provision and examine models of service delivery which could help to shift care for ADHD into primary and secondary healthcare systems, to improve healthcare access and delivery for people with ADHD. While these discussions are focused on services in the UK, the same principles are broadly applicable across many countries and regions of the world.A discussion group convened at the Royal College of Physicians in London on the 14th of June 2019. The meeting brought together primary, secondary, and tertiary healthcare practitioners with extensive experience in the clinical management of ADHD in adults, with the primary goal of evaluating the current and future potential role of primary care in the management of adults with ADHD. This was achieved by bringing together different perspectives from professionals across these healthcare sectors and identifying potential solutions for cost-effective delivery of ADHD diagnostic and treatment services. Given that ADHD presents as a common mental health problem with a wide range of severity and different levels of impairment, the discussion examined potential avenues for integrating treatment into primary and secondary care services, while being sensitive to the way in which professionals in each sector work and the pressures they deal with in their day-to-day professional lives.Attendees discussed the status and integration of ADHD in primary, secondary and tertiary healthcare in the UK, comparing different models of service delivery and their relative success. The group then considered a roadmap for improving access to ADHD treatment, by identifying issues and bottlenecks, and examining how best to bring about change in the short-term, and innovative ADHD provision in the longer-term. Discussions and recommendations were focused on adult ADHD provision in England, whilst recognising that provision and funding models vary across different regions and countries. NICE guidelines were used as a benchmark for service provision, since these provide official guidance for clinical best practice in England .Since the NICE guidelines recommend medication alongside psychoeducation as the first line treatment for ADHD, we focus in this paper on the delivery of services for the diagnostic assessment and initiating and monitoring of medication. The group recommended that psychoeducation, including the teaching of coping skills for ADHD symptoms and impairments, should be integrated into the assessment and follow-up process. Psychological treatments may also be needed, particularly for those with comorbidities, ADHD symptoms and impairments that do not respond to medication, or for individuals who do not wish to take medication.Meeting attendees included clinicians from primary care  and one nurse consultant); two health commissioning representatives; and professionals specialising in ADHD across a range of mental health professions in secondary or tertiary care . One attendee worked primarily in research, and another jointly in research and tertiary care.The initial debate from the morning session was recorded and transcribed. The transcription from the morning session was synthesised jointly by the lead author (PA) and writer (CS) and circulated to the consensus group and other members of the UKAAN executive committee . In the current document, where relevant and available, consensus discussion points are provided with reference to the supporting research literature, grey literature, policy, or legislative documentation. Draft versions of this report were reviewed by co-authors and the final draft approved by all authors prior to submission. The presented outcomes represent the consensus views of the whole group.In the early to mid-1990s in the UK, ADHD was treated in children through specialist-only tertiary clinics, and pharmacological treatment was relatively rare. Between 1995 and 2005 rates of diagnosis and prescribing for childhood ADHD increased significantly in the UK , 62. TheService provision for adult ADHD within the UK National Health Service (NHS) was initiated later than that for children. The reasons for this are not fully understood, but for a long time the validity of the diagnosis of ADHD was questioned , and ADThe publication of the NICE Clinical guideline CG72 in 2008  was a laThe publication of the 2008 NICE guidelines led to a rapid expansion in the number of clinics across England and Wales after 2008, and particularly in the last decade. Many regions set up specialist tertiary clinics for ADHD or neurodevelopmental disorders (ADHD plus autism) , althougWith increased recognition of ADHD, and improvements in service availability and provision, there has been a rapid increase in prescribing medication for ADHD , 66. HowIn children and adolescents there is also a discrepancy between the rates of ADHD treatment (0.2–0.9% since the mid-2000s ) and theScant provision for ADHD is also reflected in national surveys. A National Health Service (NHS) survey of health and wellbeing in 2014 described mental health services for adult ADHD as relatively uncommon or greatly under-resourced . The CATA 2018 audit by Takeda pharmaceuticals used data from Freedom of Information requests to survey ADHD provision in Clinical Commissioning Groups . They identified considerable regional variation in waiting times for adult ADHD assessment, from as short as 4 weeks to as long as 3.8 years . SubstanMany children diagnosed with ADHD continue to meet diagnostic criteria into adulthood , 70, andRisks to maintenance of stable treatment regimens in young people occur when at transition age they must wait for access to congested adult ADHD services, or the required specialist adult services are simply not available in their locality. Young people are more likely to experience difficulties in maintaining treatment regimens where transition is interrupted in parts of the UK where primary care practitioners do not routinely prescribe for children with ADHD but are suddenly expected to take over prescribing when they transfer to adult services. In these cases primary care practitioners may become involved in daily treatment management ‘by default’ .The clinical experts in the group agreed that for many young people who are effectively managed and on stable treatment, transfer of care can be straightforward and not time consuming. However, there will are other cases where treatment is not so straightforward, where significant continued symptoms and impairments, or additional mental health or disabilities, require further assessment and treatment.ADHD has a particularly strong negative impact on learning and educational performance, and therefore may present for the first time to student health or disability services. Within student disability services the diagnosis is often treated similarly to specific learning difficulties (SpLD), enabling students to gain access to appropriate educational support. However, providing support for students with ADHD may require a medical diagnosis, especially when the symptoms and impairments are sufficiently severe to warrant treatment with medication.To address this problem, the SpLD Assessment Standard Committee (SASC) provided guidelines in 2013 and 2021 to improve access to support for students with learning difficulties related to ADHD . SASC reRegarding pharmacological treatment, referral via their GP to specialist services for medical assessment and treatment usually results in students ending up on long waiting lists, often of 2 years or more in the UK. Long waiting lists increase the risk of academic under-performance, educational failure, or comorbid mental health conditions . It was NICE guidelines provide a comprehensive approach for assessing and managing ADHD in the NHS in England and Wales, with service organisation centred around multidisciplinary specialist ADHD teams . The guiNICE defines an ADHD specialist as a “psychiatrist or paediatrician or other appropriately qualified healthcare professional with training and expertise in the diagnosis of ADHD” . The guiThe requirement for specialism in the absence of specific guidance of who can gain this specialism and how, allows for a level of flexibility regarding who can become specialist and be relied on as a decision maker for diagnosis and treatment support. However, this flexibility also presents a lack of clarity, making it difficult to ascertain which services are best placed to deliver diagnosis and treatment for ADHD. For example, some psychiatrists take the view that specialist means a subspecialist/tertiary care service, when it could also be considered that the speciality is general adult mental health, to include ADHD. This can lead to difficulties when patients move from one region of the country to another. ADHD diagnosis and treatments formulated by a qualifying specialist in one area may not be recognised as such in another. Lack of clarity surrounding specialism also impacts commissioning services for ADHD, where commissioners can be given conflicting advice from primary, secondary, and tertiary care on the level of specialism and investment required for delivering ADHD services.It is therefore important to clarify the requirements for specialism in ADHD. Greater consistency in the definition of an ADHD specialist would allow service providers to identify and train clinical staff in the clinical management of ADHD. Furthermore, this could help healthcare services to ratify diagnoses and treatment plans to make these transferrable when patients move between services. It may also help to support healthcare commissioners, such as the current clinical commissioning groups in England, in identifying and funding services that are best placed to deliver health care provision for ADHD.Mental health professionals from a variety of backgrounds have the foundation of clinical knowledge required to acquire additional specialism in ADHD. These include different categories of professionals  from primary, secondary, and tertiary care sectors with appropriate training in adult mental health. Certain groups, such as clinical psychologists and specialists in the assessment of specific learning difficulties may be well placed to acquire additional specialism in diagnosis, and delivery of non-pharmacological interventions. Some groups such as general adult psychiatrists, primary care physicians, and mental health nurses and pharmacists could quite easily acquire the skills required for initiation and ongoing monitoring of pharmacological treatments, once diagnosis has been confirmed. Key competencies for health professionals in diagnosing and treating ADHD in adults are provided in Table Importantly, the management of ADHD is not usually more complex or difficult than other common mental health conditions currently treated within primary and secondary care. In general, those already trained to appropriately diagnose and manage other common mental health disorders, are well placed to acquire the skills required to diagnose and treat ADHD. As things currently stand, however, adult ADHD is typically not incorporated with sufficient detail in generic medical or psychiatric training. Training is therefore required under a mental health professional with clinical expertise of ADHD, or through formal training courses, such as those offered by the UK Adult ADHD Network , with apAlthough there has been considerable progress within secondary care mental health services, limited experience and knowledge of ADHD is an ongoing problem. Clinicians working with anxiety, depression, bipolar, personality and other common mental health disorders need to have a sound understanding of ADHD to ensure accurate diagnosis and optimal targeting of evidence-based treatments. Misdiagnosis leads to patients being prescribed ineffective medications for symptoms which are secondary to ADHD. For example, affective symptoms such as emotional instability, which commonly co-occur with ADHD and show good response to ADHD treatments , may be More recently, a rise in rapid poor-quality assessments leading to the inappropriate diagnosis of ADHD and initiation of ADHD medication in adults has also been noted by some specialists. This is clearly a potential problem that may increase in the future, requiring assessments to be carried out by individuals with sufficient training and expertise in the diagnosis and management of ADHD.The skills required to appropriately diagnose and treat ADHD may also be provided by appropriately trained primary care clinicians with a background and training in the diagnosis and treatment of common mental health disorders. Although currently rare, there are examples of primary care clinicians with the required competencies to diagnose and treat ADHD. Decisions to refer to more specialist services may depend on a combination of the complexity of the clinical case, the competency of the clinician, and (unfortunately) the existence of somewhere to refer them to.Straightforward cases can be diagnosed based on a clear account of current ADHD symptoms and impairments, and a history of persistent trait-like course of at least some of the symptoms from before age 12. In such cases, a diagnostic assessment may be feasible within 2 hours. Additional time is then usually required for initial psychoeducation and discussion of a treatment plan. The diagnostic assessment requires at a minimum a focused assessment at interview of ADHD symptoms and impairments, informant account from childhood where feasible, an account of the course and impact of ADHD symptoms from childhood, and assessment of common comorbidities.In other more complex or subtle cases, increased investment in time or expertise may be needed to gather more information, sometimes over more than one appointment. Like other common mental health conditions, ADHD is a heterogeneous disorder, with variations in severity of symptoms and impairments, age of onset, presentation, multi-comorbidity, and substance use and abuse.Recommended treatments include psychoeducation, psychosocial support, environmental modifications, and medication. NICE recommend that psychological treatments such as cognitive behavioral therapy are generally reserved for those who do not adequately respond to medical treatment or choose not to take medication. This guideline is based on the conclusion that the weight of evidence indicates that core symptoms of the disorder are only effectively treated with medication –92. HoweMedications for ADHD are relatively well tolerated, safe and effective . TreatmeAccess to ADHD-specific psychological interventions is very limited in NHS services and many other regions and countries. There is a clear need to incorporate training on adult ADHD into clinical psychology, nurse mental health and occupational health training. In the UK, psychological support for ADHD should be accessible through the Improving Access to Psychological Therapies (IAPT) program, which is a program for the rapid delivery of evidence based psychological treatments for common mental health disorders.NICE guidance advises that the exact balance between primary and secondary care will vary depending on the circumstances of the person with ADHD, and the available primary and secondary care services . This alAs well as variation in the types of services delivering ADHD provision, there is significant variation in how these services are organised. Examples of some of the different models of service delivery currently in use are shown in Fig. The examples provided here are by no means exhaustive but provide an indication of the different degrees of integration or segregation of ADHD across the healthcare system. Furthermore, they identify areas of vulnerability within these models, where lines of communication and cooperation between separate services can break down, and demand can start to outstrip service resources.Within the NHS in England, variation in ADHD service provision is influenced by regional differences in regulation and funding allocation. Local prescribing formularies, put together by a local committee of health professionals under each healthcare commissioning body  can prohIn England, many other issues in delivery of medical treatments for ADHD arise, which likely play a role in many other regions and countries. Compliance with local formularies may be enforced on a primary care service level by Medicines Management Teams. They can hold back funding for primary care services where they fail to adhere to local prescribing guidelines. In some areas, prohibitions from local prescribing formularies have been imposed suddenly, leaving primary care practitioners exposed to challenge when attempting to maintain treatment for their patients. The national contract states that primary care prescribers must prescribe what they think is the best treatment within the limits of their competence, however the local healthcare commissioning groups may advise them not to prescribe some drugs for ADHD. The General Medical Council says that doctors should prescribe a licenced drug rather than an unlicensed equivalent where possible. There are clearly competing and overlapping agendas, and a general lack of clarity in this area in England, which are likely reflected elsewhere.Resource limitations can reduce capacity for primary services to support shared care in ADHD treatment monitoring and prescribing. Even when formularies allow prescribing and primary care representatives agree that pathways are clinically appropriate, some practices argue they lack capacity to accept shared care arrangements without additional funding. Additional training also requires funding.Primary care practices typically have an ‘indicative budget’ and ‘medicines management’ is typically part of a local ‘Prescribing Incentive Scheme’. Each regional healthcare commissioning body decides how to run its own budgets, and this can mean regionally divergent rules on what primary care practices must do to receive incentives. This usually includes some ‘quality’ issues such as audits to show the appropriateness of prescribing , but may also include keeping within the indicative budget. An average sized practice which fails to meet requirements for a local medicine management scheme, may miss out on funding in the order of several thousand pounds. Further, if the regional healthcare commissioning body exceeded its budget, they are required to make cuts or claw back funds from other areas of healthcare. This is a complex process which varies between regions.In regions of England without adult ADHD services, individuals should by right, be able to access these services elsewhere. A patient’s legal “right to choose” the providers of their care was introduced in 2014 and updated in 2018 . With thADHD in adults often presents within primary care with complaints of poor functioning or performance, educational or occupational failure, emotional instability, anxious worrying, mood symptoms or sleep problems. ADHD is also associated with increased rates of general health conditions such as obesity, type II diabetes, asthma, hypercholesterolaemia, hypertension and smoking and its consequences , 96–98. There is increasing evidence that improved management of ADHD can help a range of co-occurring health problems, in addition to reducing the core symptoms and impairments of ADHD. For example, ADHD is associated with treatment resistance in comorbid depression  which maPharmacotherapy for ADHD does appear to be a protective factor for obesity , communiConsistent with these findings is the evidence that treating ADHD in adults reduces health care and other public services use costs further down the line , 32, 102Improving capacity for managing ADHD by primary care clinicians who are already tasked with managing a range of health conditions commonly comorbid with ADHD, could help to improve health outcomes more broadly and result in longer-term savings. Arguably, effective management of ADHD could reduce overall work volume due to the positive impact of other mental and physical health issues, resulting in better utilisation of GP resources.As discussed above, NICE guidance recommends that ADHD can be managed and monitored jointly between specialists and primary healthcare, under shared care protocols . As recoSometimes shared care arrangements are drawn up by secondary or tertiary services, or healthcare commissioners, without sufficient primary care input. Some primary care practitioners are concerned about this shift in workload from secondary to primary care without additional or sufficient resources . FundingNot all primary healthcare practitioners support shared care protocols, and in some areas primary care will not take up the responsibility for physical monitoring and continued prescribing. Sometimes GPs will point out this not part of their contract and they are not funded for this work. Primary care practitioners may also have valid concerns about taking on clinical responsibility for an unfamiliar treatment and disorder , particuRoutine follow-up of ADHD patients is not simply a matter of monitoring physiological parameters, but also of understanding how the condition is currently impacting on the person’s life, including the impact of treatment (or non-treatment) on any comorbidity, and the provision of psychosocial support where required. According to NICE, a formal review needs to be carried out at least annually, by a clinician with a good understanding of this condition. Adequate training and support for primary care practitioners is therefore needed to support routine follow-up, with access to specialist ADHD services for ongoing advice as required.Even in the context of shared care arrangements, demand for resources from specialist teams increase with every newly diagnosed patient. A large population study from Sweden found that following initiation of medication for ADHD, 75% of adults were still receiving medication after 1 year, 60% after 2 years, 50% after 3 years, and 42% after 4 years . AssuminRoutine annual reviews of patients take up an increasing portion of finite clinical capacity. Over time, clinics with no growth in funding or staff resources see the service getting clogged up with routine annual reviews, constricting resources for not-yet diagnosed or treated patients. This issue, coupled with increasing rates of referral resulting from increasing public and professional awareness of the condition and the high prevalence of ADHD, have led to demand outpacing provision, and in turn to very long waiting lists.A hybrid specialist service, which transfers annual treatment reviews to qualified staff within primary care can help to reduce incremental resource demands on secondary health services. As described previously, most primary healthcare practitioners are well qualified to obtain the adequate training and supervision required for long term monitoring of ADHD. Annual treatment review for straightforward cases within primary care would allow secondary care to focus more on new patients and those with a more complex clinical presentation. The annual reviews could be completed by primary care clinicians with specialism in ADHD, such as specialist mental health nurses, psychologists, pharmacists, or general practitioners with a special interest in ADHD  contract with primary care is to assess and treat or refer people who may be unwell. Chronic disease monitoring and preventive care is part of the Quality and Outcomes Framework (QoF), but is optional, and currently attracts funding for provision of specific areas of care that do not include ADHD. Moreover, the QoF framework does not provide a catch-all for all follow-up and long-term monitoring requirements. Resource allocation for ADHD treatment monitoring could be provided by incorporating funding for care of ADHD under the QoF in a similar way to funding for diabetic care. Similarly, it would be possible to set up a “Direct Enhanced Service” as an addition to the core GMS contract, with its own national funding.Currently, if a healthcare commissioning group wishes to fund care for ADHD locally, it is possible to set up a “Local Incentive Scheme”  to fund primary care to support monitoring as part of shared care. There are issues surrounding equity of access unless all practices sign up to provide this service, and the healthcare commissioners must decide where else to divest to fund the scheme.The precise model or contractual framework may be much less important than the political will to address the needs of the population with ADHD. The will to improve provision for mental health more generally is confirmed, at least on paper. The ‘Community Mental Health Framework for Adults and Older Adults’ 2019  mentionsFurther mainstreaming of adult ADHD by incorporating it more into general adult mental health services, is likely to have an important impact on enhancing access to diagnosis and treatment. As discussed, a key initial change to service organisation would see the transfer of routine annual medication monitoring to primary care for patients with a positive and stable response to their treatment regimen. Referral for more specialist input would be only where there is a specific issue or area of unmet need, including the delivery of psychosocial interventions. A related model could see referral to, for example, nurse led teams that sit between primary and secondary care, for long term monitoring of the disorder, again with onward referral as required. Nurse and psychology led services may be better at providing ongoing psychoeducation and psychosocial support in addition to monitoring of medication,Formal training and accreditation for specialism in ADHD diagnosis and treatment could be arranged through primary care training hubs, or with support from professional membership bodies, such as the Royal College of GPs or the Royal College of Psychiatrists in the UK. Initially this may be particularly important for primary care staff, for whom involvement in adult ADHD management is currently less common than for secondary or tertiary care staff.In the longer-term, a care pathway modelled on the NICE stepped care model for anxiety disorders and depression , 113 couPrimary care ADHD services could also be incorporated within Primary Care Networks (PCNs). These are part of the NHS Long Term Plan published in 2019 , which dIncreasing knowledge about ADHD within multidisciplinary primary care practitioners would have a powerful role in improving ADHD provision. Teams can work together to reach consensus when the threshold of complexity is reached. Accessibility and clear lines of communication to ADHD specialists is needed.An important component of primary care mental health are psychological services. In England, so called IAPT Services  typically provide psychological therapies for adults with anxiety disorders and depression , but curWhilst the last two decades have seen a stepped change and increase in the provision of adult ADHD clinical services in the UK and elsewhere, demand currently outstrips provision by a long way in many regions and countries. Growing awareness of the condition in the public and clinical community has led to increased referrals for adult ADHD. Trends showing yearly increases in ADHD treatment in the population , coupledPeople with ADHD are vulnerable to other concurrent mental health problems, alcohol and drug use problems, educational and occupational impairments, accidents and injuries, communicable diseases, and involvement with the criminal justice system , 41, 117At the heart of the problem, we find a trio of interrelated constraints. The first pivots on the interpretation and understanding of ‘ADHD specialists’, who are responsible for delivering a range of services to support adults with ADHD . Whilst In the current paper we review NICE guidelines and conclude that adult ADHD specialist support can be delivered at primary, secondary, or tertiary level, assuming appropriate levels of professional training and supervision. Adopting a more inclusive view of ‘ADHD specialists’ can help to improve access to treatment for patients by broadening sources of clinical expertise.The second constraint is organisational. Where there is over-reliance on the limited capacity secondary and specialist services, these rapidly become overwhelmed when treating this common and often chronic condition resulting in bottlenecks. Transfer of routine clinical care  to primary care providers through shared care protocols can help to alleviate some of this strain on capacity and should occur as standard clinical practice. However, even in the context of effective shared care protocols, ADHD specialist clinics with no growth in funding or staff resources often become clogged up with routine annual reviews and become unable to accommodate new referrals in a timely fashion.The third constraint is financial. Different commissioning arrangements for primary and secondary healthcare can lead to tensions regarding transfer of routine care between services, particularly for patients with ADHD in whom pharmacological treatments are often provided long-term and are more expensive than for other mental health conditions. Limits to budgets and competing demands from different parts of the healthcare sector results in a reluctance to take on additional work, with ADHD often falling between services. There is no cost neutral solution which will solve the capacity issue and therefore models should not be built around cost-saving or cost-shifting, but rather a longer-term perspective built around the question ‘what does good care look like?’Although the focus on services in England is a potential limitation of this paper, the issues raised are widely experienced and are of general relevance to service development for ADHD in many other regions and countries.Mainstreaming straightforward cases of ADHD into primary care could enhance access to diagnosis and treatment for this common condition, improve the health and wellbeing of adults with ADHD, and reduce the burden of co-occurring problems and conditions on the broader health system. These changes to ADHD service delivery should be supported by patient consultation, to examine their perspectives on service models and preferences as to where and how their care is managed , 120.Changes to operational models could be supported by formal training and accreditation for specialism in adult ADHD. An initial change to service organisation would see the transfer of routine annual medication monitoring duties  to primary care for patients with a positive and stable response to their treatment regimen, and referral back to specialist services only in instances when treatment requires attention or modification.ADHD Specialism embedded within primary care will also help to facilitate transition from child to adult services, by maintaining ADHD management until adult services are available.For students with ADHD, student disability teams and trained specialist assessors who complete diagnostic assessments for ADHD should collaborate with clinical services for ADHD. Their assessments can then form part of the medical assessment through appropriate collaboration with either a student secondary care mental health service or trained health care professionals within primary care. An ADHD service embedded within primary care, especially at surgeries located within university health centres, can offer a cost-efficient pathway for university students with ADHD.In the longer-term, ADHD treatment and management should be brought in line with care pathways for other common mental health disorders, where primary care practitioners with expertise in ADHD take over treatment initiation and titration for patients with more straightforward clinical presentations. Referral to generic mental health or specialist services is indicated for more complex cases. The management of uncomplicated adult ADHD could follow the model of other common mental health problems, which has become core business of primary care and IAPT over the last 20 years.Such developments would require greater resourcing for mental health within primary care. It is unrealistic to expect each primary care service to have an in-house ADHD specialist, but plans for more joined up and flexible provision and funding arrangements hold promise for improvement in the delivery of ADHD services. Collaborating practices, using a primary care network approach, can invest in developing shared ADHD specialist resources across a larger area which serve a larger portion of the population. In turn, with support from appropriately experienced and qualified primary care networks, individual primary healthcare providers may be better supported to take on routine treatment and follow-up assessments, and broader facets of ADHD management and treatment.Based on these discussions the group made a set of recommendations for the future development of primary care services for adults with ADHD:


Background: Increasing evidence supports a neuroinflammatory basis in ADHD damaging glial function and thereby altering dopaminergic (DA) neurotransmission. Previous studies focusing on the S100B protein as a marker of glial function have shown contradictory results. We conducted a clinical trial to investigate differences in S100B levels between ADHD patients and controls, as well as observe gradual changes in S100B concentrations after a triple therapy (TT) containing methylphenidate (MPH), melatonin (aMT) and omega-3 fatty acids (ω-3 PUFAs). Methods: 62 medication-naïve children with ADHD (ADHD-G) and 65 healthy controls (C-G) were recruited. Serum S100B was measured at baseline (T0) in ADHD-G/C-G, and three (T3) and six months (T6) after starting TT in the ADHD-G, together with attention scores. Results: A significant increase in S100B was observed in the ADHD-G vs. C-G. In the ADHD-G, significantly higher S100B values were observed for comparisons between T0–T3 and between T0–T6, accompanied by a significant improvement in attention scores for the same timepoint comparisons. No significant differences were found for S100B between T3–T6. Conclusion: Our results agree with the hypothesis of glial damage in ADHD. Further studies on the link between DA and S100B are required to explain the transient increase in S100B following TT.  Attention-deficit and/or hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents, characterized by the impairing presence of inattention, hyperactivity, and impulsivity . Its worThe pathophysiology of ADHD is not completely understood. Core symptoms have been linked to disruptions in the maturation of the cerebellum, caudate and prefrontal cortex (PFC). These areas create a network involved in the regulation of executive functions  ,9,10, anThe mechanisms leading to the catecholaminergic disruption observed in this disorder are multifactorial  and yet The cytokine-related neurotrophin S100B, mainly secreted by astrocytes and oligodendrocytes, is a well-known biomarker of glial function . At nanoVariations in S100B levels have been associated with neuropsychiatric diseases for which a redox imbalance and inflammatory basis are proposed . SignifiNowadays, increasing evidence supports a neuroinflammatory origin of ADHD, as an association was found with single-nucleotide polymorphisms (SNPs) in genes involved in angiogenesis and inflammation . MoreovePsychostimulants, and particularly the different formulations of methylphenidate (MPH), continue to be the first-line pharmacological treatment for ADHD. MPH blocks the presynaptic DA and NE transporters that respectively reuptake these neurotransmitters, thus facilitating catecholaminergic neurotransmission . HoweverBased on the interaction with DA/NE neurotransmitters and the pro-inflammatory actions of S100B, we support that this protein may act as a mediator in the neuroinflammatory mechanisms leading to the catecholaminergic disruption preceding ADHD symptoms. Accordingly, we hypothesized that: (1) S100B concentrations in pediatric patients with ADHD should differ from controls; and (2) variations in S100B levels should accompany the clinical response of ADHD patients with a triple therapy consisting of MPH, aMT and ω-3 PUFAs. In this dual three-month-phase clinical trial on children and adolescents with ADHD, we aimed at (1) evaluating differences in serum S100B levels between ADHD patients and healthy controls; and (2) assessing gradual changes in both serum S100B concentrations and clinical symptoms (as per attention scores) after initiating treatment with a combination of MPH, aMT and ω-3 PUFAs.We designed a two-year-duration, single-center, open-label clinical trial on children and adolescents with ADHD. Medication-naïve children and adolescents between 6 and 15 years old who had recently been diagnosed with ADHD in accordance with the DSM-5 criteria  and wereA control group composed of age- and sex-matched healthy children was also recruited following the same exclusion criteria. They were children and adolescents attending the hospital for routine blood extraction and free of cardiologic, neuropsychiatric, metabolic, or endocrine disorders.Initial clinical interview and physical examination were supported by the application of the following questionnaires as part of the diagnostic workup for ADHD: (1) the NICHQ Vanderbilt Parent and Teacher Assessment Scales ,56; (2) The CDI is a self-report assessment of depression for children and adolescents between 7–17 years old. It contains two subscales: negative mood and negative self-esteem. For each item, the respondent is presented with three choices that correspond to three levels of symptomatology: 0-absence of symptoms; 1-mild or probable symptom; 2-definite symptoms. A quantitative cut-off > 18 (normative T-score > 50) is considered pathological . The CDIMSVA is a psychometric tool designed to evaluate several attentional functions: focusing, maintaining, coding and stability. The patient is exposed to visual stimuli during a certain period (6 min in children under 9 years of age and 12 min in those older) while a simple motor task is performed by asking them to identify the figure of a man described within a grid full of distracting stimuli in the form of human figures in other postures or rotations. By quantifying the number of correct responses, commission errors, and omission errors, two variables are obtained: sustained visual attention (SA) [SA: (correct responses + omissions)/total n° of correct responses)] and quality of attention [QA: (correct responses – omissions − commission errors)/(correct responses + omissions)] . While t® . The assay sensitivity was 30 µg/L.Fasting venous blood samples were collected in the morning (08.00–09.00 h). After centrifugation, the serum was separated and frozen at −80 °C. Protein S100B was measured through the sandwich enzyme-linked immunosorbent assay (Sandwich ELISA), which uses a capture antibody and a detection antibody conjugated with isoluminol. The equipment was provided by LIAISONThe following combination (triple therapy) was administered: (1) prolonged-release MPH (OROS formulation), given in the morning at an initial dose of 0.7 mg/kg/day that was adjusted according to response and treatment; (2) aMT, administered at 3 mg/night 30 min before usual bedtime; and (3) a combination of ω-3 PUFAs, consisting of eicosapentaenoic acid (EPA) at 70 mg/day and docosahexaenoic acid (DHA) at 250 mg/day. We decided to use the QA/SA scores from the MSVA as objective indicators of the clinical response to therapy, based on previous studies reporting on the effects of MPH and ω-3 PUFAs on omission and commission errors ,61. Applt-test to make comparisons between controls and ADHD patients, and an analysis of variance (ANOVA) and Bonferroni post-hoc test for comparisons across time within the ADHD group. The non-parametric Friedman test was applied to compare SA/QA scores at T0–T3–T6 in the ADHD group. The significance level was set at α = 0.05. Descriptive data were presented as mean . Comparisons were made for S100B levels between the ADHD group and the control group, as well as for the values of SA/QA and S100B in ADHD patients at T0–T3–T6. For comparative analyses, the Kolmogorov-Smirnov test was applied to verify the normality assumption. Parametric tests were used for comparisons in S100B levels: a Student’s The Statgraphics Centurion version XVII software  was used for statistical calculations.The study protocol was approved by the Ethics Committee of Biomedical Research at San Cecilio University Hospital . All procedures were carried out in accordance with the Declaration of Helsinki, as revised in 2013 .Sixty-two children and adolescents with ADHD participated in the study. The ADHD group was composed of 41 males (66.13%) and 21 females (33.87%), with a mean age of 9.26 (2.11) years. In accordance with the DSM-5 criteria  and at T6 . No significant differences were observed, however, for comparisons of QA and SA values between T3 and T6  at T0 vs. 0.89 (0.12) at T3 ] (Serum S100B levels were significantly reduced in the control group compared to ADHD patients at T0 [control group: 0.0938 (0.035) μg/L vs. ADHD group: 0.2204 (0.089) μg/L at T0 ( 0.001)] .p < 0.001)], as well as significantly higher S100B concentrations at T6 compared to T0 [S100B mean values: 0.2204 (0.089) μg/L at T0 vs. 0.3408 (0.1527) μg/L at T6 (p < 0.001)]. No significant differences in S100B values were found between T3 and T6  μg/L at T0 vs. 0.3339 (0.1447) at T3 . Intergroup comparisons (ADHD-I vs. ADHD-C) across time revealed no significant differences in S100B levels. However, when analyzing the evolution of S100B values across time for the patients included in the same ADHD presentation , differences between T0–T3, T0–T6, and T3–T6 followed a similar pattern to the one observed for the whole group .In this clinical trial on a sample of medication-naïve children and adolescents with ADHD, peripheral S100B levels were measured with two main objectives: (1) to establish comparisons with healthy children as controls; and (2) to observe gradual differences in serum S100B values in the ADHD group before (T0) and after (T3–T6) treatment with a triple therapy containing MPH, aMT and ω-3 PUFAs (EPA/DHA). Secondarily, we also reported the clinical effects obtained with this therapy based on the attention measures obtained in the MSVA and the reports from parents/guardians and teachers. At baseline (T0), we found significantly higher levels of S100B protein in the ADHD group compared to control participants. Focusing on the patients with ADHD, a significant increase in S100B values was observed when comparing the levels of this protein before treatment onset with those three and six months after starting therapy. However, S100B values at T3 and T6 were similar. The two components of attention, QA and SA scores, also showed a significant improvement after three and six months of therapy in relation to baseline values (T3 vs. T0 and T6 vs. T0), with no significant changes observed when comparing QA/SA scores between three and six months after treatment onset. When comparing S100B values between ADHD patients and controls, our results differed from the first studies presented by Oades et al.  and lateThe finding of significantly higher peripheral S100B concentrations in patients with ADHD in relation to non-related controls in our study is in line with the hypothesis of global neuroinflammation leading to the dopaminergic disruption observed in this disorder. A pro-inflammatory state in the brain would activate astrocytes, which would react by releasing S100B and activating the NF-kB-dependent inflammatory cascade through the interaction between S100B and RAGE ,25,26,27The most striking result was a paradoxically significant increase in S100B concentrations three months after starting therapy (T3) compared to baseline (T0) in the ADHD group, at the same time that a significant improvement in the attention scores (QA/SA) was also observed. In the study conducted by Fernández-López et al. , a non-sOur study contained several limitations: first, the design did not allow us to observe the relative effect on S100B due to MPH, whereas a clinical trial with different treatment arms would have provided information on the impact of each therapeutic component on this protein; second, we lacked evidence on the response triggered by this treatment in patients with a pure hyperactive/impulsive presentation, as the sample only included patients classified as predominantly inattentive or combined; third, the application of more flexible exclusion criteria with respect to the prior investigations conducted by Oades et al.  and FernTo date, this is the first trial reporting on gradual changes in peripheral S100B levels in children and adolescents with ADHD receiving a triple therapy containing MPH and the anti-inflammatory combination of aMT and EPA/DHA. The differences observed between patients with ADHD and controls provide evidence in line with the glial damage leading to dopaminergic disruption and consequent ADHD symptoms ,73. No cOur study revealed significantly higher peripheral S100B levels in patients with ADHD compared to controls, strengthening the hypothesis of glial damage within the mechanisms preceding the catecholaminergic disruption responsible for this disorder. Therapeutic administration of MPH, aMT, and ω-3 PUFAs was followed by a paradoxical transient increase in S100B levels, that would require further investigation in future trials with different treatment arms and longer follow-up periods.


Attention-deficit/hyperactivity disorder (ADHD) is a childhood neurodevelopmental disorder that can persist into adulthood. The co-occurrence of ADHD and substance use disorders is very frequent and has received considerable attention in recent clinical/scientific investigations. However, few studies have investigated the prevalence of ADHD in heroin addicts. This study aimed to investigate the prevalence of attention-deficit/hyperactivity disorder (ADHD) in a sample of heroin addicts treated with opioid agonists and to report this clinical experience in a public service for addiction. Outpatients over 18 years old and being treated with opioid agonists for heroin addiction were enrolled. Each patient took part in a psychiatric examination and completed an ASRS  self-assessment. Subjects with positive results were called in for another psychiatric visit, and the Brown ADD scale was used as a second-level test for ADHD; furthermore, the Mini International Neuropsychiatric Interview (MINI) and Hypomania/Mania Checklist (HCL-32) were used for differential diagnoses and to assess comorbidities. In total, 111 patients were enrolled. All were followed up by the psychiatrist, who is also the author of this report and the person who formulated the diagnoses. The prevalence of ADHD in this sample was 18%. Among the 20 patients diagnosed with ADHD, 5 (25%) were female and 15 (75%) were male. The most frequent psychiatric comorbidity was major depression, found in 11 patients (55%), of which 4 presented with hypomania (bipolar disorder). In this sample, making diagnoses was very difficult. Frequently, multiple comorbidities further complicated these cases. In conclusion, the results of this study are consistent with the literature: There seems to be a significant prevalence of ADHD even among heroin addicts, and often, the diagnosis is difficult to make. We also do not know the exact effect of opioid agonist therapy on ADHD symptoms. Hypotheses have been put forward, but studies are needed. Attention-deficit/hyperactivity disorder (ADHD) is a childhood neurodevelopmental disorder characterised by inattentiveness and impulsivity, which can be associated with hyperactivity; it also persists into adulthood in two-thirds of cases .The population prevalence of adult ADHD is reported to be 3–5%   is higher in adults with ADHD than in the general population ,4. AccorThe co-occurrence of ADHD and substance use disorders has received considerable attention in recent clinical and scientific investigations because it is very frequent and has serious clinical implications     assessments were used. The authors found that about 23% of the participants were likely to have ADHD. However, the aim of the study was to correlate ADHD with psychopathology and impulsivity. The authors reported that, in ADHD patients, substance use disorder may facilitate impulsive acts. The authors did not specify whether self-harm also increases in these patients, especially if they also have mood disorders [In 2017, an Italian multicentric study was published in which 1057 heroin addicts in opioid treatment completed the ASRS for ADHD and the SCL-90. About 19% of the participants screened positive for concurrent adult ADHD symptoms. Unfortunately, this study only evaluated ADHD symptoms (which are frequent in drug addicts) and did not verify the ADHD diagnosis [This Italian study, conducted with patients in the public addiction service, has the merit of focusing attention on this type of patient.The author of this study also works in a public addiction service in which the majority of patients are addicted to heroin. Clinical observation often leads to the suspicion of ADHD, but there are no specific and shared protocols to identify such subjects. It is important to identify these patients so as to improve the management of their addictions. For this reason, a protocol very similar to that used in normal clinical practice was devised, at a low cost and with immediate results.For practical reasons, the need arose in the clinical context, and not in a research university, to evaluate the prevalence of ADHD in heroin addicts being treated with opioid agonists.The purpose of this report is to detail this experience and the results so as to give food for thought and research.This study was conducted at a public addiction treatment centre  in Castelfranco Veneto, Italy. As mentioned in the introduction, it is a public centre of the National Health Service. These centres deal with addiction and are multiprofessional . This service was implemented in Italy in the 1970s–1980s when heroin became a major problem; they are today rather well-regarded in this sense.Castelfranco’s service only operates on an outpatient basis, and those receiving treatment are predominantly heroin addicts.The subjects in this sample had the following characteristics:DSM-5 [Adult outpatients diagnosed with opioid use disorder according to the criteria listed in the DSM-5 .All patients had been on maintenance therapy  for at least 6 months. Prior years of treatment ranged from 6 months to 30 years. Most of these patients had been engaged in therapy for at least 10 years (44.1%).No participant was being treated with ADHD therapy (methylphenidate or atomoxetine), either before or during agonist treatment.None of the participants had been diagnosed with ADHD in childhood. .All of the patients in this centre, without exception, entered into treatment voluntarily and signed an informed consent form, as is a part of our normal practice.Psychiatric visits and the prescription of therapy are part of the routine practice of the service. The tests used in this study are also routinely used in our clinical practice. They were only used more systematically for the purposes of this study. As already mentioned in the introduction, the study was designed to be as similar as possible to our normal clinical practice, with a very low cost, easy application, and immediately accessible data.All of the enrolled patients received a psychiatric visit, and the Adult ADHD Self-Report Scale (ASRS v1.1) was administered . The visThe first test used was a screening test: the Adult ADHD Self-Report Scale (ASRS v1.1):DSM criteria, but they have been reworded to better reflect symptom manifestation in adults. This scale is useful for the screening and diagnosis of ADHD among adults above 18 years of age and should be used in conjunction with a clinical interview to provide additional clinical information.The Adult ADHD Self-Report Scale (ASRS v1.1) is an 18-item self-report questionnaire designed to assess attention-deficit/hyperactivity disorder (ADHD) symptoms in adults (18+ years of age). This scale is based on the World Health Organization Composite International Diagnostic Interview (2001), and the questions are consistent with “Part A: contains 6 items and it has been found that these questions are the most predictive of ADHD and are best for use as a screening instrument. Part-B: contains 12 additional questions based on DSM criteria that provide additional cues and can serve as further probes into the patient’s symptoms. For a client’s symptoms to be considered consistent with an ADHD diagnosis, they require 4 or more responses at specific severity levels in Part A of the ASRS” ; it has been validated and is widely used in clinics and in research studies   for adults .(1)Organisation, establish priorities;(2)Focus, support, and shift attention;(3)Regulation of activation, support the effort;(4)Manage frustration and modulate emotions;(5)Working memory and re-enactment; and(6)Monitor and self-regulate the action.The Brown ADD scale for adults evaluates symptoms attributable to attention-deficit disorder (ADD). It consists of several sections, including an anamnestic part and a psychiatric comorbidity part, that are administered via semi-structured interviews. It also includes a self-administered section of 40 items and the comparison of the patient’s answers with those of a family member or acquaintance. The self-administered items can be grouped into six clusters:An explanation of these parameters is contained in the test manual, and these parameters were applied in the present study .Brown-scale-positive patients were then given other tests for the differential diagnosis: the MINI and the HCL-32.DSM-4 criteria, and it is used both in clinics and in research studies [DSM-4), and at the end, the clinician can indicate whether a category has been satisfied. The diagnostic categories considered in the test are as follow: major depressive episode with or without melancholia, dysthymia, suicide risk, (hypo)maniac episode, panic, agoraphobia, social phobia, generalized anxiety disorder, obsessive–compulsive disorder, posttraumatic stress disorder, and substance addiction, and there is an optional antisocial personality module.The Mini International Neuropsychiatric Interview (MINI v5.0.1) is a diagnostic rating scale. It includes a semi-structured interview compatible with  studies . The intThe Hypomania/Mania checklist (HCL-32) is a self-rating questionnaire designed to assess a lifetime history of hypomanic symptoms   was administered; the MINI and HCL-32 were also administered so as to aid in the differential diagnosis. This ended the diagnostic process. A control group was not foreseen. This study aimed to observe the prevalence of ADHD in a common clinical practice procedure. All psychiatric visits and testing were performed by the same psychiatrist.In total, 111 patients participated in the study; 89 were male (80.1%), and 22 were female (19.8%). The average age of the participants was 38.9 years.The following socio-demographic parameters were taken into consideration: sex (m/f);age;marital status (single/married/divorced or separated);educational attainment (primary/lower secondary/secondary–university);employment ;cohabiting ; andclarification: lives with children (yes/no),It can be seen that this sample was mostly made up of single people with a low–medium educational level. Most had stable jobs and lived with their parents.Types of secondary substances used were also taken into consideration, as reported by patients and confirmed by urinary toxicology tests.All patients smoked cigarettes (tobacco) (100%).The second-most frequently used substance was cocaine, alone (24.3%) or with the same frequency as another substance . This affected almost half of the patients (42.3%).Cannabinoid use was also frequent throughout the sample alone (19.8%) or with other substances , totalling 36%.As one can see, alcohol was often associated with the use of other substances; alone, it affected 8.1% of patients.The use of amphetamines and MDMA were infrequent in this sample: 1.8%.A total of 4.5% of patients reported engaging in polysubstance abuse, i.e., the abuse of more than two secondary substances.A total of 22.5% of the patients were in treatment with agonist therapy without a secondary substance .Of the 111 patients, 83 (74.4%) scored negative on the ASRS. However, 15 of these were suspected of having ADHD  based on clinical observation, and they continued in the study.A total of 68 of 83 patients were excluded because they were assessed as negative for ADHD.A total of 28 patients (25.2%) out of the 111 respondents tested positive on the ASRS, and they continued on to the second phase of the diagnostic study. However, 6 ASRS-positive patients failed to enter the second phase due to dropout. Thus, 22 patients (19.8%) remained. These 22 positive-ASRS patients, combined with the 15 suspected false-negative patients, made up a total of 37 patients who underwent the second part of the study.These 37 patients participated in another psychiatric visit, and they were administered the Brown ADD scale. Six patients tested negative on this assessment. Another 11 tested negative but borderline for ADHD; that is, some requirements were missing, but they had many ADHD characteristics.Finally, 20 patients tested ADHD positive .Among the 20 patients diagnosed with ADHD, 5 (25%) were female, and 15 (75%) were male.The scheme of study and the results are shown in ; 20% of these cases came with a diagnosis of bipolar disorder; 35% showed lifetime major depression without a diagnosis of bipolar disorder. Anxiety–panic disorders affected 35% of the patients. The diagnosis of antisocial personality disorder was associated with 25% of the cases.The MINI also assesses the risk of suicide. The risk was present in 20% of these patients.A total of 40% of patients had at least two other psychiatric diagnoses in addition to the diagnoses of substance use disorder and ADHD.This study was conceived in a clinical context, not in a research centre or a university. This centre treats many heroin addicts. In our clinical practice, ADHD symptoms are very frequent; some research has confirmed this observation. For us, it is very important to understand whether these symptoms correspond to a diagnosis of ADHD for practical reasons: we need to plan more targeted interventions and therapies. For this reason, a protocol was designed that is practical and relatively easy to apply so as to understand how many patients actually present with a diagnosis of ADHD.The diagnostic study of ADHD in drug-addicted patients is very difficult for several reasons. One of these is that the presence of substance use can induce secondary ADHD symptoms and confuse the clinical presentation. Substance use alters cognitive modalities, causes attention deficits, and affects cognitive flexibility, working memory, and impulsivity management, similarly to ADHD . The difWe must take this into account, but it should not stop us from looking for an answer. We have a duty to do this for these patients.In this study, an attempt was made to enrol a slightly more stable category of patients. Among drug users, those who use heroin as their primary drug and are receiving agonist treatment generally appear more stabilised. From this group, patients who had been in treatment for at least 6 months were chosen. Moreover, almost all of these patients were in the stabilisation phase at the time of observation; only a few were in the disengagement phase (on discharge from the service).The presence of agonist therapy and the treatment phase were chosen to try to eliminate as much interference from the use of substances as possible; this interference could not, of course, be ruled out, but at least it was reduced.The psychiatric examination of the patients was conducted by the same physician for the duration of the study; this was the same doctor who treats these patients in the facility and knows them. This ruled out the possibility of a double-blind study, but it was preferred as an aid to the differential diagnosis.The patient sample was not randomised, and it has particular characteristics. The patients belong to a public, outpatient facility. In Italy, there is a very widespread public treatment network, and most of the patients who use heroin enter the public service. Only the public service can provide agonist therapy to these patients. The choice of patients treated with agonists allowed access to a large sample of heroin addicts. However, it must be taken into account that participation in this study was voluntary; it is likely that has resulted in the selection of less-severely affected patients.Another limitation of this study is that not all enrolled patients were followed up to the end. This prevented the comparison of the positive and negative ADHD groups.As far as the tests are concerned, they were chosen from those that are most commonly known and used in Italian psychiatric and addiction services. The ASRS is a very common and easy-to-use screening scale; the Brown scale is among the most-used for diagnosis in second-level testing.For the differential diagnosis, we chose the MINI, which includes all of the main psychiatric diagnoses and, above all, it is easy to use.The HCL-32 scale, which is also very practical, is used for the diagnosis of bipolar disorder, which is often associated with, or can be confused with, ADHD.At the end of the diagnostic process, an ADHD frequency of 18% was found. It is a frequency compatible with the data as published in the literature; this encourages us to think that this method could be effective in clinical practice.Our results seem to confirm that, even among heroin-using patients, there is a significant percentage of people with ADHD, and this is very important for the prognosis, course, therapy, and organisation of services.Interestingly, there were six dropouts among the ASRS-positive patients during the study. This number corresponds to 5.4% of the total sample, but also to 30% of the ASRS-positive sample. We do not have a ASRS-negative group comparison; nonetheless, we expect ASRS-positive individuals to be more impulsive and more severely affected, so they would be more likely to exit the program. However, we think that this could be a useful field for future investigation.We report that it was very difficult to diagnose ADHD in these patients for several reasons.We know that ADHD is more difficult to diagnose in adults, notably because the presentation of symptoms changes in adulthood. The presence of substance use disorder seems to be a further complication.The effect of the substances, as stated above (symptoms secondary to substance use).The anamnestic reconstruction. .The collaboration of family members. .The patients’ own recognition of symptoms. ADHD patients usually have little insight. This was a very obvious problem. All of the patients in the study were assisted in completing the self-administered tests. They were assisted by the same psychiatrist who had them in his charge, and he knew them well. The psychiatrist saw that they did not recognize their symptoms on the test, and it was often necessary to cause them to reflect and give examples. On the other hand, the presence of a psychiatrist who knew the patients could have influenced the results.High comorbidity. Other disorders may alter the presentation of symptoms.We had diagnostic difficulties mainly due to:DSM diagnosis and/or had borderline test results), we often wondered if agonist therapy might be playing a role. We know that it stabilises heroin addiction, exerts an anticraving effect on other substances, and has other effects on psychopathological symptoms ; however, we do not know if it also stabilises ADHD symptoms by making them weaker.In evaluating patients with borderline symptoms of ADHD  . We noteAnother unsurprising figure is the high percentage of patients who were assessed as being at a risk of suicide on the MINI (20%). We know that ADHD patients display less self-control, and this facilitates self-harm. Additionally, the risk of suicide in these patients seems to have been considered rarely in the literature. In our opinion, this topic deserves further study.This study was conducted in a public addiction service where there was a need to diagnose ADHD patients for better clinical practice. The literature is limited, so a protocol with resources and tools normally available in the service was applied. The purpose of this report was to demonstrate this clinical practice experience and to show the results of the prevalence of ADHD in these patients. The intent was also to raise awareness of the problem and provide ideas for future research.In this sample, the prevalence of ADHD was found to be 18%; this result is consistent with that found in the literature. The psychiatric comorbidity data are also compatible with those found the literature. Affective disorders appeared to be the most frequently associated psychiatric disorders in this sample. Multiple comorbidities very frequently appeared, and there was a high percentage (20%) of subjects who were at risk of suicide.We report that it was very difficult to diagnose ADHD in these patients. Strategies were sought to help with the anamnesis and to support the poor insight of the patients. An attempt was made to reduce the interference of substances. However, the problem of diagnosis remains difficult to solve.We have also brought attention to the role of agonist therapy, asking the question of whether it can improve symptoms associated with this disorder. It would be important to understand this therapy better, which does not yet seem to have been taken into consideration in the literature.Another focus was placed on the suicide risk of these patients, a worrying fact that deserves more attention. The risk of suicide in drug addicts has rarely been studied. In theory, ADHD-affected drug addicts, often having lower self-control, should be at even greater risk. However, this hypothesis needs to be proved.The difficulties of studying these patients, at the level of clinical practice and even more so in systematic research, must not stop us. On the contrary, these difficulties must stimulate us even more to seek answers.


This study aims to investigate the prevalence estimate of diabetes mellitus (DM) among people with attention deficit hyperactivity disorder (ADHD) as well as the prevalence of ADHD among those with DM. In addition, the impact of ADHD on glycemic control in patients with DM was also assessed using a systematic review and meta-analysis of currently available published data.The PubMed, Embase, Web of Science, and PsycInfo databases were searched for potential studies. Two reviewers independently selected studies according to the inclusion and exclusion criteria. All pooled analyses were conducted using the random-effects models on Review Manager 5.3.Seventeen observational studies were included. The pooled results showed an increase in the prevalence of DM among patients with ADHD versus those without ADHD . There was an overall 35% increase in the prevalence of ADHD among patients with type 1 DM [OR: 1.35 (95% CI: 1.08–1.73)]. Children with type 1 DM and ADHD had higher levels of hemoglobin A1c [standardized mean of differences: 0.67 (95% CI: 0.48–0.86)], and prevalence of hypoglycemic and ketoacidosis index compared with those without ADHD.Our study revealed the bidirectional associations between ADHD and DM. Patients with ADHD and type 1 DM comorbidities were more likely to have poorer diabetes control. More studies are needed to confirm this association and elucidate the underlying mechanism. Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder characterized by inattention and/or hyperactivity/impulsivity, leading to poor academic and social outcomes, with prevalence rates ranging from 3 to 7% , 2. In aDiabetes mellitus (DM) is a common metabolic disease characterized by elevated blood glucose levels. The main subtypes of DM are type1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Several studies have found bidirectional associations between ADHD and DM. In a longitudinal study of all diabetic children in Germany/Austria between 2003 and 2015, the percentage of ADHD in patients with T1DM ranged from 1.91 to 2.93% . FurtherThis study was performed according to the PRISMA guidelines, the Cochrane Handbook for Systematic Reviews, and the Ottawa Non-Randomized Studies Workshop –13.The search strategy was designed to address the following question: “Is there an interrelationship between ADHD and DM?” The search was completed on November 23, 2021, using the following electronic databases: PubMed, Ovid EMBASE (1947 to present), Web of Science, and PsychInfo. The search terms included “DM”, “T1DM”, “T2DM”, “attention-deficit disorder”, “attention deficit”, and “hypersensitivity” see . The refTwo authors (YA and TZ) conducted the study selection, and any disagreement was settled by discussion with a third author (JZ). A flow diagram is provided in Observational studies  that reported the prevalence of diabetes among patients with ADHD or that reported ADHD among diabetes patients were considered eligible for this study. Studies that compared glycemic control in patients with DM with and without ADHD were also included. The indexes of glycemic control were hemoglobin A1c (HbA1c) level, frequency of hypoglycemia, and ketoacidosis. Eligibility was not limited by the type of DM. Studies that included neonates, studies without distinguishable comparison groups, and studies that did not report prevalence data or provide original data to calculate were excluded. If more than one study reported the same outcome indexes using data from the same study subjects, the study with more comprehensive results was selected.We extracted the following information from the included studies: first author names, publication year, country, study design, sample size, participants’ age, ADHD assessment, and diabetes assessment. For studies reporting the prevalence of ADHD or diabetes, data sufficient to complete a 2 × 2 contingency table and any reported adjusted prevalence odds ratios (ORs) were extracted. For studies comparing glycemic control, we extracted HbA1c (means and standard deviations), and the presence of acute complications, such as diabetic ketoacidosis (DKA) or hypoglycemic attacks.We employed the Newcastle-Ottawa Scale (NOS) to evaluate each eligible study . This sc2 statistics and the Q-test method  existed among the included studies, we only calculated the pooled prevalence estimate using ORs and 95% confidence interval (CI) based on the random-effects model, as recommended by the Ottawa Non-Randomized Studies Workshop . A secont method . If I2 ≥The systematic literature search and study selection details are shown in the I2 = 64%, p = 0.04)  . The pooI2 = 92%, p < 0.01; None of the studies have assessed the risk of ADHD in patients with T2DM. Five studies evaluated the risk of T2DM in patients with ADHD compared to those without ADHD. The pooled results showed that a higher proportion of patients in the ADHD group had T2DM compared with the control group  between T1DM patients with ADHD and those without ADHD . Pooled DKA was performed in 48 cases and 246 controls in .Type 1 diabetes mellitus (T1DM) patients with ADHD had a significantly higher prevalence of hypoglycemia than those without ADHD (OR 2.29, 95% CI: 1.04–5.03, trols in . The pooThe asymmetric shapes of the funnel plots indicated the existence of publication bias in the selected studies.To our knowledge, this is the first study to evaluate and consolidate the literature on the association between ADHD and diabetes. Significant heterogeneity was identified between the prevalence estimate and mean difference studies. The population of interest, sample size, and adjustment for potential confounders appeared to have been an important source of heterogeneity. Our pooled analyses suggest an important comorbid relationship between diabetes and ADHD. Overall, there was an increase in T2DM of 166% and 51% in children and adults with ADHD, respectively, relative to those without ADHD. An overall 37% increase in T1DM was observed in children with ADHD. In addition, 35% of the children with T1DM also met the criteria for ADHD.The results from the second meta-analysis in T1DM patients detected an overall pooled SMD in HbA1C levels between children with ADHD and those without ADHD. Despite the high level of heterogeneity among these studies, no further subgroup analysis was conducted owing to the small number of studies included. Further analyses identified higher hypoglycemia and DKA index rates within the ADHD groups compared with their non-ADHD counterparts.The mechanisms underlying the association between diabetes and ADHD are unclear. Most studies have focused on the prevalence of T2DM and neurologic diseases among middle-aged and elderly individuals, and there is little information available regarding this effect among children and adolescents. Diabetes is a group of metabolic syndromes characterized by hyperglycemia. The disturbance of blood glucose can lead to a series of pathogenetic mechanisms involving neurological dysfunction, including neuronal apoptosis, abnormal energy metabolism, synaptic dysfunction, neurodegenerative changes, and oxidative stress in brain tissue –34. CompSeveral factors may be involved in the association between ADHD and diabetes. Evidence emerging supports the role of maternal diabetes in neurocognitive and behavioral difficulties in their offspring, including ADHD –44. ExpoFurthermore, we found patients with T1DM and ADHD had poor glycemic control. There may be many ways ADHD impacts an individual’s ability to control diabetes. Previous studies have shown that typical symptoms of ADHD not only lead to a higher risk of DKA but also increase the risk of severe hypoglycemia , 47. TheThis meta-analysis has certain limitations. First, the majority of the included studies were not cohort studies. Based on the evidence gathered, we could only speculate on the possible coexisting conditions between ADHD and DM; the onset and the causative pathways between the two conditions could not be identified. Second, we only included studies published in English. The number of studies and sample size were insufficient. We could not perform a subgroup or meta-regression analysis to determine whether the association may or may not be influenced by other factors. Our study’s findings should be interpreted in light of statistical analysis limitations in a small sample. Third, marked heterogeneity was observed across the results of the included studies. This may be due to differences in population selection, the sample sizes of the studies, and outcome measure assessments. For example, five studies , 20, 30 This systematic review and meta-analysis evaluated studies exploring the association between ADHD and DM. It is important for doctors who treat people with ADHD or DM to be aware of the comorbid association between ADHD and DM. Our study suggests that children with T1DM and ADHD are more likely to have poor glycemic control than those without ADHD. Furthermore, Liu et al. suggested an increased risk of diabetic nephropathy and nephropathy in patients with T1DM and ADHD . This asThe original contributions presented in this study are included in the article/YA and TZ: conception of the work, literature search, and drafting the article. YA, TZ, and HL: data analysis. JL and HL: critical revision of the article. All authors final approval of the version to be published.