To examine if the clinical feasibility and effectiveness of apsychoeducational program targeting children’s ADHD differ between parentswith varying ADHD symptom severities.An open trial analyzed data from 549 parents of children with ADHD aged 3 to17 years, who participated in psychoeducation at an outpatienthabilitation/disability clinic. In all analyses, parents were stratifiedinto three symptom severity groups (low/middle/high) based on scores on anADHD screening scale.Parental ADHD symptom severity was not associated with results on anyoutcome, although the odds of having incomplete data were higher in parentsreporting higher symptom severity. Across the entire sample, we observedhigh program completion rates, positive acceptability ratings and largeincreases in parental knowledge.Psychoeducation may be beneficial regardless of the participating parent’sADHD symptomatology. Further research is needed to examine whether theseresults are generalizable to parents diagnosed with ADHD, anunderrepresented group in our study. ADHD is a neurodevelopmental disability characterized by a persistent pattern ofinattention, disorganization, and/or hyperactivity-impulsivity that causes functionalimpairment across most areas of life . ThepreTreatment guidelines generally recommend that the assessment of children’s ADHD befollowed by structured information about the diagnosis and its treatment . ChildreThe accessibility of an intervention has implications for its clinical feasibility,including completion rates and program acceptability. Psychoeducation is most oftendelivered in a standardized educational group format, where didactic lectures form acentral part . PsychoeWhen it comes to the effects of parent-received psychoeducation, its positive role hasbeen supported across several trials . The finThe objective of this study was to examine whether the clinical feasibility (in terms ofcompletion rates and acceptability) and effectiveness of a parent-receivedpsychoeducational program on children’s ADHD differ between parents with varying ADHDsymptom severities. The program under study is widely implemented across Sweden, withgood clinical feasibility . HoweverThis open trial was performed at the ADHD Center, Habilitation & Health,Region Stockholm, Sweden. The ADHD Center is a publicly-funded outpatienthabilitation service clinic that offers courses, workshops, and lectures on ADHDfor families of children and adolescents with ADHD, aged 3 to 17 years.Throughout the Stockholm region, families of children who have been diagnosedwith ADHD following procedures for a formal ADHD assessment  are recoThe project was approved by the Regional Ethics Committee in Stockholm(2017/575-31/5). Participants received information about the study and itsprocedures in written and oral format before giving their written consent.A total of 585 parents of children and adolescents with ADHD aged 3 to 17 yearswere recruited from among families enrolling in the psychoeducational programunder study at the ADHD Center. Of these, the 549 participants (93.9%) that hada complete baseline rating on the Adult ADHD Self-Report Scale (ASRS) Screenerwere included in further analyses . Of the The recruitment period lasted between May 2017 and November 2019. The recruitmentprocedure was further adapted at two occasions, due to clinical routine changesat the ADHD Center and a low initial participation rate. Initially, all parentswho signed up for the program under study were invited to also participate inits evaluation . Later, some  program rounds were dedicated to the evaluation in such a waythat all parents who signed up for these particular course rounds alsoparticipated in the study . Parents recruited before and afterthe routine changes did not differ in regard to their baseline ASRS Screenerscores (p = .18).The structured psychoeducational program under study is developed for parents ofchildren (4–12 years) and adolescents (13–17 years) with ADHD. An earlierversion of the program received positive evaluations in a trial of ADHDpharmacotherapy delivered in combination with psychoeducation and the Supplemental Table 1). Lectures are held for groups of 25 to 35parents, guided by a detailed manual and slide presentation. At the ADHD Center,each lecture is delivered by a clinical psychologist. A total of 15psychologists with program-specific training were involved in the currenttrial.The program consists of five 3-hour lectures providing information about ADHD,treatment options and societal support services, as well as environmentalmodifications and parenting strategies that may facilitate the everydaymanagement of the target child’s needs and behaviors  participated and 42.5%of lectures were observed. Across the monitored lectures, all (100%) of themanualized content was delivered during 94.1% of the occasions .In addition, all (100%) criteria related to program structure adherence andprovision of material were fulfilled during 82.4% of the observed lectures. Thetreatment integrity ratings were made by a research assistant (psychologystudent), using standardized checklists.worstpossible) to 10 (best possible). The program’sclinical feasibility was evaluated based on program completion rates and ratingsof program acceptability. The program’s effectiveness was examined byself-report questionnaires, completed at baseline (pre) and immediately after(post) the intervention.Participants completed a questionnaire covering a range of sociodemographicfactors and rated their own overall well-being on a scale of 1 (never) to 4 (very often).Responses are then dichotomized, yielding a score between 0 and 6. Tofurther enhance the usefulness of the ASRS Screener in reproducing clinicalADHD evaluations, scores are collapsed into three strata: low (correspondingto scores 0–1), middle (scores 2–3), and high (scores 4–6). Using thesestrata, rα = .81.The Adult ADHD Self-Report Scale (ASRS) is an ADHD screening scale designedto measure the frequency of recent adult ADHD symptoms . The shoCompletion rate: Attendance was documented continuously. Parentsattending at least four  of the five lectures were considered tohave completed the program.Acceptability ratings: Lecture acceptability and satisfactionwas evaluated with a treatment evaluation scale  to 3 (yes absolutely). Three itemstargeted lecture contents  and a fourthaddressed the experience of in-lecture discussions. A summary lectureevaluation score was calculated by averaging each respondent’s ratingsacross items, with higher mean scores (ranging between 0 and 3) taken toindicate a more positive appraisal. Overall program satisfaction wasevaluated with an extended version of these lecture evaluation forms,completed after the program. In addition to items addressing the overallcontent relevance, usefulness, and in-lecture sharing of experiences, thescale was supplemented with a summary grade  and a question of whether the participant wouldrecommend the program to other parents. Once again, items were rated on ascale ranging from 0 to 3, and a higher mean score (ranging between 0 and 3)was taken to indicate a more positive appraisal of the program. Cronbach’salpha was rα = .80 for the overall program satisfactionscale and varied between rα = .74 and rα =.81 for the five lecture satisfaction scales.on scale  modifiedKnowledge quiz: The participants’ knowledge about ADHD,treatment options, societal services, and parenting strategies  was measured with a modified version ofan ADHD quiz  scored on a true-,false-, or don’t know-scale and threeshort-answer questions . Each correct answer wasassigned one credit, yielding a total sum score between 0 and 20. Higherscores were taken to indicate more knowledge. When administered in thecurrent sample, the Knowledge Quiz was found to have good discriminantproperties, reaching a post intervention average item-difficulty of p = .75, thus meeting the ≥ .75 threshold often set forfalse/true tests  of the Knowledge Quiz was KR20 =.63.DHD quiz . This 20ue tests . The intStrengths and Difficulties Questionnaire (SDQ): The generalbehavioral symptoms and attributes of the participants’ target children weremeasured with the extended version of the SDQ for parents of 4 to 17year-olds  and can be summed toyield a total score between 0 and 40. The SDQ also comprises a five-itemprosocial behaviors subscale, with sum scores ranging from 0 to 10.Moreover, the SDQ has an impact supplement that asks parents to rate theextent to which their child’s difficulties cause distress or socialimpairment: not at all, only a little,quite a lot, or a great deal . When summed, this SDQ Impact Score rangesfrom 0 to 10. Overall, higher scores indicate more difficulties , more prosocial behaviors , or moreeveryday impairment (Impact Score). In the current sample, Cronbach’s alphawas rα = .68 for the Total Difficulties Scale,rα = .73 for the Prosocial Subscale, andrα = .72 for the Impact Score.ear-olds , 1999. TThe Parental Stress Scale (PSS): The participants’ levels ofparental stress were measured with the PSS (I feel overwhelmed by theresponsibility of being a parent) rated on a 5-pointLikert-type scale from 1 (strongly disagree) to 5(strongly agree). Responses are summed to yield a totalPSS score between 18 and 90. Higher scores indicate higher levels ofparental stress. In the current sample, Cronbach’s alpha wasrα = .84. the PSS . The scaParental attributions (PA): The participants’ causalattributions about undesired behaviors displayed by their target child weremeasured with a modified version of the Written Analog Questionnaire . Next, parents were askedto think about a situation where the stated behavior occurred in a typicalmanner and rate their assumptions about its causes on six 10-point scalesfrom 1 to 10, addressing the following: the causal locus, the stability andthe globality of the behavior, the child’s degree of control over thebehavior, the intentionality of the behavior, and the parent’sresponsibility for the occurrence of the behavior. Then, parents were askedto do the very same thing once again, while rating the assumed causes forthe second most troublesome behavior of their target child. In line withpreviously published procedures , controllable or intentional, and of one’s own parentalresponsibility for the occurrence of the behavior as beinglower. In the current sample, Spearman Brown split-halfcoefficients were estimated to .50 for one of the two-item PA dimensions(Controllability) and seen to vary between .62 and .67 for the others .The extent of missing data was substantial post intervention, which is why wepost hoc chose to analyze the potential associations between dataincompleteness and parental ADHD symptom severity. Scales missing ≤10% ofitem scores were treated as complete after item-level imputation: missingKnowledge Quiz items were replaced with a value (credit) of 0, while missingSDQ and PSS items were replaced with the average of the respondent’sobserved items. Pairwise exclusion was used to handle scales missing >10%of items, as well as missing sociodemographic data.Based on the assumption that adults with a positive ADHD screening are morelikely to experience impairment, we wanted to differentiate between parents whoreported high ADHD symptom severity (screening positively for ADHD) and parentswho did not. Accordingly, participants were stratified into groups correspondingto the low, middle, and high strata defined by The odds of completing the program were examined in a binary logistic regression,using the ADHD strata variable as predictor. A series of one-way ANOVAs wereconducted to examine whether parents scoring in the low, middle, or high ADHDstrata differed in their ratings of lecture or program evaluations, or in termsof baseline scores on the effectiveness-related measures. Significant effectswere further investigated using Tukey’s post hoc tests.time  as within-subjects factor andgroup  as between-subjectsfactor. Due to the significant amount of missing data, the primary analyses wereperformed per protocol (including only complete cases). They were then repeatedaccording to the intention-to-treat (ITT) principle (including programcompleters as well as non-completers with pre-intervention data), with missingvalues replaced using the last observation carried forward procedure. For thesake of brevity, results from these secondary ITT analyses are reported indetail only when they differ significantly from results obtained per protocol.The same applies to the supplementary analyses in which parents’ and children’sbaseline medication status were included as covariates. Cohen’sd was interpreted as 0.20 = small, 0.50 = medium, and 0.80= large (np2)was interpreted as .01 = small, .06 = moderate, and .14 = large  scored in thelow ADHD stratum, 144 (26.2%) scored in the middle ADHD stratum, and 106 (19.3%)scored in the high ADHD stratum . Among the 22 parents (4%) who reported that they currently had anADHD diagnosis, 2 (9.1%) scored in the low ADHD stratum, 4 (18.2%) scored in themiddle, and 16 (72.7%) scored in the high.Parents in the low, middle, and high ADHD strata differed in terms of educationallevels, proportion working full-time, and ratings of their own well-being , but notAt baseline, parents in the high ADHD stratum reported higher parental stressthan parents in the low attending at least four  of the five lectures . For parents scoring in the low, middle,and high ADHD strata, the completion rates were 90%, 84.3%, and 86.8%,respectively. Using parents in the low ADHD stratum as reference, the oddsof completing the program were not significantly lower in the middle  or in the high ADHD stratum . There were no significant differencesbetween program completers and non-completers in terms of ASRS Screenerscores (p = .24) or when compared across a range of demographic variablessuch as age, gender, education, main occupation, child age, and child gender(p = .13 to .81).pass with distinctionor higher (95.5%). There were no statistically significant differencesbetween parents in the three ADHD strata, neither in terms of lectureacceptability ratings (p = .15 to .81), nor in terms of program satisfaction(p = .60).Overall, lecture evaluations were positive, averaging 2.7 on a 0 to 3satisfaction scale (SD = 0.4). Ratings of the five lectures varied between M= 2.6 (SD = 0.4) and M = 2.7 . Ratings of overallprogram acceptability averaged 2.7 on a 0 to 3 scale .Almost all parents stated that they would probably or absolutely recommendthe program under study to other parents (99.8%) and gave it a final summarygrade equivalent to a school grade of p2 = .56, p < .001) and no between-stratadifferences .The results did not change when parent and child medication status wereincluded as covariates.When analyzed per protocol, there was a significant main effect of time,revealing a large increase in parental knowledge from pre to postintervention . The results did not changewhen parent and child medication status were included as covariates, withtwo exceptions: the small pre-to-post change on the PA Responsibilitydimension did not survive (p = .08) and the interaction effect for the PAControllability dimension got significant .When analyzed per protocol, parents reported small but statisticallysignificant changes (reductions) in the behavioral and symptomaticdifficulties of their target child (SDQ), their own levels of parentalstress (PSS), and their causal attributions about undesired behaviorsdisplayed by their target child PA; . The onlSupplemental Table 2). The average number of lecture evaluationforms missing for parents in the low, middle, and high ADHD strata was 0.9 (SD =1.2), 1.2 (SD = 1.4), and 1.2 (SD = 1.3) out of five, respectively. Theproportion of participants lost to post-intervention measurements was 16.1% inthe low, 22.2% in the middle, and 17.9% in the high ADHD strata. The averagenumber of effectiveness-related post-intervention measures missing for parentsin the low, middle, and high ADHD strata were 0.82 (SD = 1.5), 1.1 (SD = 1.7),and 1.0 (SD = 1.6) out of four, respectively. The proportion of participantsthat missed at least one post-intervention measure was 25.1% in the low, 33.3%in the middle, and 31.1% in the high ADHD strata.The amount of missing data varied between variables but was generally smaller inthe low ADHD stratum than in the middle and high strata .Using parents in the low ADHD stratum as references, post hoc analyses revealedthat the odds of missing at least one lecture evaluation form were higher amongparents in the high ADHD stratum .Likewise, the odds of missing at least one effectiveness-related outcome measurewere higher in the middle  and in thehigh ADHD stratum , although only thefirst result was statistically significant  was much smaller than the expected 20% to 40%.Looking first across the entire sample, the results regarding the clinicalfeasibility and the informative utility of the psychoeducational program under studywere promising. When administered in its current outpatient habilitation servicescontext, including a range of inclusive practices to promote accessibility, no lessthan 88% of the participants completed the program. Also in support of the program’sclinical feasibility, the parents’ evaluations of its acceptability were noticeablypositive. In terms of program effectiveness, the findings were consistent withprevious observations of improvements in parental knowledge followingpsychoeducation . In contContrary to what was hypothesized, the clinical feasibility and effectiveness of theprogram under study did not differ between parents with varying ADHD symptomseverities. Instead, parents with high ADHD symptom severity were found to be aslikely to complete the program, submit positive program acceptability ratings, anddisplay knowledge gains as parents with low ADHD symptom severity. The main findingsof this study thus differ from previous research linking parental ADHD symptoms andexecutive dysfunction to parenting- and treatment-related difficulties , includiFirst, based on these promising results, it seems that the overall accessibility ofthe program under study may indeed be sufficient for a large proportion of parentsenrolling in psychoeducation at the ADHD Center. However, it remains unclear whetherthese results would apply more generally, to psychoeducation delivered with feweradult ADHD adaptations or to a sample with other demographic characteristics.Second, it may be that parental ADHD symptoms do not influence psychoeducationoutcomes in a way that is comparable to how they seem to attenuate the effects of,for example, parent training interventions . For exaThird, as is often the case in clinical research , wemay The results of this uncontrolled study should be read in the light of theabove-discussed limitations in sample representativeness, which do haveconsequences for their generalizability to parents with diagnosed ADHD.Furthermore, it should be noted that the amount of missing data was unevenlydistributed in such a way that a disproportionally large percentage of parentswith higher ADHD symptom severity had to be omitted from many analyses. Thispattern of missingness is not surprising given drop out and data incompletenessrates in other clinical trials where adults with ADHD symptomatology participatein interventions directed to themselves  ortargeOur results indicate that parents with varying degrees of ADHD symptomatology,including those with high symptom severity, may indeed benefit from parent-receivedpsychoeducation delivered with general adaptations to promote program accessibilityfor adults with ADHD. Further research is needed to examine whether these resultscan be generalized to parents with diagnosed ADHD and significant impairments ineveryday functioning, whose ADHD symptom burdens are higher than those observedamong parents in the current study.Click here for additional data file.Supplemental material, sj-pdf-1-jad-10.1177_10870547221092120 for Is Parents’ADHD Symptomatology Associated With the Clinical Feasibility or Effectiveness ofa Psychoeducational Program Targeting Their Children’s ADHD? by ThereseLindström, Axel Kierkegaard Suttner, Martin Forster, Sven Bölte and TatjaHirvikoski in Journal of Attention Disorders


Recently, there has been an increase in telemedicine applied to child neuropsychiatry, such as the use of online platforms to collect remotely case histories and demographic and behavioral information. In the present proof-of-concept study, we aimed to understand to what extent information parents and teachers provide through online questionnaires overlaps with clinicians’ diagnostic conclusions on attention-deficit/hyperactivity disorder (ADHD). Moreover, we intended to explore a possible role that autism spectrum disorders (ASD) symptoms played in this process. We examined parent- and teacher-rated questionnaires collected remotely and an on-site evaluation of intelligence quotients from 342 subjects , aged 3–16 years, and referred for suspected ADHD. An easily interpretable machine learning model—decision tree (DT)—was built to simulate the clinical process of classifying ADHD/non-ADHD based on collected data. Then, we tested the DT model’s predictive accuracy through a cross-validation approach. The DT classifier’s performance was compared with those that other machine learning models achieved, such as random forest and support vector machines. Differences in ASD symptoms in the DT-identified classes were tested to address their role in performing a diagnostic error using the DT model. The DT identified the decision rules clinicians adopt to classify an ADHD diagnosis with an 82% accuracy rate. Regarding the cross-validation experiment, our DT model reached a predictive accuracy of 74% that was similar to those of other classification algorithms. The caregiver-reported ADHD core symptom severity proved the most discriminative information for clinicians during the diagnostic decision process. However, ASD symptoms were a confounding factor when ADHD severity had to be established. Telehealth procedures proved effective in obtaining an automated output regarding a diagnostic risk, reducing the time delay between symptom detection and diagnosis. However, this should not be considered an alternative to on-site procedures but rather as automated support for clinical practice, enabling clinicians to allocate further resources to the most complex cases.The online version contains supplementary material available at 10.1007/s00787-023-02145-4. Over the 10 past years, healthcare services have been involved in a progressive digitalization process . AccordiOur proof-of-concept study addresses this topic regarding a diagnosis of attention deficit / hyperactivity disorder (ADHD) because the evaluation process for this condition reflects the trend toward digitalization described above. According to the National Institute for Health and Care Excellence Guidelines , an accuWithin this workflow, ADHD characteristics are investigated—to a certain degree—through parent and teacher reports that could be digitally administered. A recent study demonstrated that parents and teachers showed similar diagnostic accuracy in predicting a clinical diagnosis when considering the ADHD Rating Scale-IV threshold to discriminate ADHD/non-ADHD condition . HoweverThe present study has two objectives. First, we aimed to understand to what extent expert clinicians’ diagnostic conclusions overlap with the information parents and teachers provide via online questionnaires. To do this, we tested a decision tree (DT) classification, which is an interpretable machine learning (ML) algorithm, to analyze diagnostic data collected at the Scientific Institute “IRCCS Eugenio Medea” Regional Center for ADHD . Here, wSecond, we intended to explore whether caregivers reported a co-presence of autism spectrum disorder (ASD) symptoms. We aimed to understand at which point the presence of autistic features in children clinically referred for ADHD problems could represent a potential confounding factor, also taking into account the considerable behavioral overlap between the two disorders , 16.In this retrospective, single-center, observational study, we reported data from the diagnostic process of a sample of children and adolescents referred for suspected ADHD diagnosis at the Scientific Institute “IRCCS Eugenio Medea”—Associazione La Nostra Famiglia in Bosisio Parini —between early 2017 and late 2020. The Institute’s Ethical Review Board  approved this study and all the participants’ legal guardians gave their written informed consent to the children’s participation.DSM-5 criteria [Participants included 342 children and adolescents  living in Northern Italy, aged 3 to 16 years, who underwent a full neuropsychiatric evaluation and did or did not receive an ADHD and/or ASD diagnosis in accordance with the criteria .A workflow of the diagnostic procedure is shown in Fig. Case history and demographic questionnaire. The following information was collected: (a) age and sex; (b) perinatal risk factors, including pregnancy problems, preterm or late birth, extremely high or low birth weight, breastfeeding problems, and APGAR score at birth; (c) family type ; and (d) family socioeconomic status coded according to the Hollingshead scale [ad scale .Parent-report questionnaires. Conners' Parent Rating Scale–Revised (CPRS-R) [(CPRS-R) . The CPR(CPRS-R) . CPRS-R Child Behavior Checklist (CBCL) for Ages 1.5–5 or CBCL for Ages 6–18 , 21. TheSocial Responsiveness Scale (SRS) . The SRSTeacher-report questionnaire. Conners’ Teacher Rating Scale–Revised (CTRS-R) [(CTRS-R) . The CTRA medical doctor specialized in child neuropsychiatry fully examined all participants. A child psychologist with experience in ADHD and ASD independently confirmed the diagnosis via direct observation of the child and administered neuropsychological and cognitive tests.Intelligence quotient evaluation. The child’s IQ was evaluated through one of the following scales according to age, testability, and ability: Griffiths Mental Development Scales [t Scales ; Wechslet Scales ; and Wect Scales .Statistical analyses were performed using R version 4.1.2 .To ascertain which reported features held the most relevance in the diagnostic process of ADHD, we used a DT classifier, which is a flowchart-like structure that is built considering the full data set “sitting” at the top of the root node, and at each junction, observations satisfying the splitting condition are assigned to the left branch and the others to the right branch . InformaTP means true positive: the subjects who the clinicians diagnosed with ADHD and who the DT correctly classified as “ADHD”;TN means true negative: the subjects who the clinicians did not diagnose with ADHD and who the DT correctly classified “non-ADHD”;FP means false positive: the subjects who the clinicians did not diagnose with ADHD and who the DT wrongly classified as “ADHD”;FN means false negative: the subjects who the clinicians diagnosed with ADHD and who the DT wrongly classified as “non-ADHD.”Note that:Classification accuracy: percentage of correctly performed predictions against the total number of instances.No information rate (NIR): the accuracy achievable by always predicting the majority class label.P-Value of Acc > NIR: a hypothesis test result to evaluate whether the algorithm’s classification accuracy is greater than the rate of the largest class (NIR).Specificity: percentage of correctly performed negative predictions (non-ADHD) against the number of subjects without an ADHD diagnosis.Sensitivity: percentage of correctly performed positive predictions (ADHD) against the number of subjects with an ADHD diagnosis.Positive predictive value (PPV): percentage of subjects with an ADHD diagnosis against the number of all positive predictions (ADHD).Negative predictive value (NPV): percentage of subjects without an ADHD diagnosis against the number of all negative predictions (non-ADHD).The algorithm performance was evaluated considering the following information .ClassifiTo evaluate the generalization performances of each ML-trained model, a leave-one-out (LOO) cross-validation technique was used because it provides an accurate estimate of the probability of error . FurtherClassifications of ADHD/non-ADHD diagnoses the DT algorithm performed were compared with the clinicians’ actual ADHD/non-ADHD diagnoses. To address the clinical characteristics of subjects the DT algorithm incorrectly classified , the whole data set was split into ADHD and non-ADHD children. Correct/incorrect classification was the dependent variable in two further ML models to identify a rule-based algorithm that could express the properties of misclassified subjects. ML analyses were performed as previously described.Moreover, correct/incorrect classification was an independent variable and socio-demographic and cognitive information were dependent variables in non-parametric analyses to address whether these factors could be associated with the DT model’s performance.To disentangle the role of ASD symptoms in the DT algorithm’s correct/incorrect classification, subjects with or without an ADHD diagnosis were considered separately in two contingency tables addressing frequencies of correctly/incorrectly classified ADHD by the DT and the presence versus absence of an ASD diagnosis as the clinicians assessed. Two Fisher’s exact tests were applied to test the association between receiving an ASD diagnosis and being correctly or incorrectly classified as ADHD through the DT algorithm.In addition, parent-reported ASD symptoms were evaluated regarding the correctly classified/misclassified ADHD subjects. TP/TN/FP/FN categories independent variables and the six SRS scores were dependent variables in separate Kruskal–Wallis tests. To identify what specific couples of medians were significantly different, two-sided pairwise Wilcoxon Rank Sum tests with Bonferroni correction for multiple comparisons were performed. The following group comparisons were considered: (a) TP versus FN and (b) TN versus FP.After performing data cleaning procedures (see the Supplementary Information section), more than 50% of data were missing for 16 subjects, which we therefore excluded from the analyses. The final sample consisted of 326 children and adolescents. Table Figure Table Correct (TP and TN) and incorrect (FP and FN) classifications were considered in the two groups of clinician-diagnosed ADHD and non-ADHD, separately.Figures Tables Table Lastly, socio-demographic and cognitive information did not result significantly different between the DT-identified classes.Table The Kruskal–Wallis tests by ranks were all significant, except for the Social Motivation problems scale. Autism symptoms were reported higher in the TP group compared to the FN group, and in the FP group higher compared to the TN group. Hence, the DT algorithm highlighted a tendency toward an ADHD diagnosis when parents reported elevated ASD symptoms.Figures Over the last few years, the digital innovation process and the COVID-19 pandemic have spurred an increasing request for telehealth procedures , 38. TheThe present study’s first aim was to explore whether and to what extent expert clinicians’ clinical diagnosis of ADHD agreed with symptoms that parents and teachers rated through online-administered questionnaires. To this end, we tested a DT, given its notable interpretability and the suitability for digitally collected data . Our algDSM-oriented ADHD scales of both the informants showed a crucial relevance for the clinicians’ diagnostic decision. This is interesting considering that the DT assigns the same “weight” to all the considered input variables . Moreover, although the algorithm was totally naïve about the questionnaire cutoffs, in the upper nodes, the DT identified scores that were in line with moderate and severe risk for ADHD, respectively 64 and 70 [As expected, among all the collected measures, the core parent- and teacher-reported ADHD symptom severity was the most discriminative information for the DT classification. Ratings on 4 and 70 , 24. The4 and 70 .Notably, in 18% of the cases, clinicians reached a different diagnostic conclusion compared to that resulting from the parent report-based algorithm. This result is in line with Tahıllıoğlu and colleagues’ (2021) recent findings, which reported that, in 16% of the cases, parent reports were not in line with the diagnostic conclusion clinicians made on the presence or absence of ADHD in a sample of boys [The second aim of this study was to understand whether the co-presence of ASD symptoms as the caregivers described could represent a potential confounding factor, given the considerable overlap in symptom presentation . In our It is important to remember that the DT only relied on caregivers’ reports of ADHD core symptoms and often associated oppositional symptoms . As expeConsistently, the analysis of social abilities among the four groups the DT sorted showed that participants with higher ratings of social cognition, communication problems, and autistic mannerisms on SRS were classified as having ADHD, leading to many FPs for the algorithm. These traits, with the addition of social awareness, were conversely lower in children the algorithm misclassified as non-ADHD. Despite representing a novelty for what concerns the analytic approach, this finding may corroborate previous evidence. Indeed, social functioning atypicalities, a hallmark of ASD, are often reported in ADHD as well . AlthougOnline information collection and screening procedures should not be merely considered as an alternative to on-site diagnostic practice. Instead, telehealth can help effectively collect reliable caregivers’ reports and obtain a subsequent automated output regarding a diagnostic risk factor . SpecialSome limitations of the present preliminary study should be considered. Our sample included children and adolescents from the same area  that their pediatricians referred for suspected ADHD. Moreover, the sample is composed of males in a greater proportion compared to females; despite this being in line with literature, it could have represented a bias within our statistical models. Thus, our results might not be generalized to different populations. Furthermore, our analysis exclusively addressed the potentially confounding effects of autism symptoms in ADHD classification. However, there are several conditions commonly associated with ADHD . AdditioFuture research focused on developing online platforms for remotely performed data collection is needed . DevelopSupplementary file1 (DOCX 47 KB)Below is the link to the electronic supplementary material.


Children with attention-deficit/hyperactivity disorder (ADHD) symptoms often experience social and emotional problems. Impaired facial emotion recognition has been suggested as a possible underlying mechanism, although impairments may depend on the type and intensity of emotions. We investigated facial emotion recognition in children with (subthreshold) ADHD and controls using a novel task with children’s faces of emotional expressions varying in type and intensity. We further investigated associations between emotion recognition accuracy and social and emotional problems in the ADHD group. 83 children displaying ADHD symptoms and 30 controls (6–12 years) completed the Morphed Facial Emotion Recognition Task (MFERT). The MFERT assesses emotion recognition accuracy on four emotions using five expression intensity levels. Teachers and parents rated social and emotional problems on the Strengths and Difficulties Questionnaire. Repeated measures analysis of variance revealed that the ADHD group showed poorer emotion recognition accuracy compared to controls across emotions . The significant group by expression intensity interaction  showed that the increase in accuracy with increasing expression intensity was smaller in the ADHD group compared to controls. Multiple regression analyses within the ADHD group showed that emotion recognition accuracy was inversely related to social and emotional problems, but not prosocial behavior. Not only children with an ADHD diagnosis, but also children with subthreshold ADHD experience impairments in facial emotion recognition. This impairment is predictive for social and emotional problems, which may suggest that emotion recognition may contribute to the development of social and emotional problems in these children.The online version contains supplementary material available at 10.1007/s00787-020-01709-y. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders. This disorder is characterized by symptoms of inattention, hyperactivity, and/or impulsivity . AlthougRecent work has focused on emotional dysregulation as a feature of heterogeneity in ADHD –14, suggd = 0.49) and fear (d = 0.48) effects sizes were moderate; for sadness (d = 0.24) and happiness (d = 0.22) they were small. Another factor that may underlie the inconsistent findings regarding emotion recognition abilities in ADHD is comorbidity with conduct problems: Three recent studies showed no impairment for the recognition of any emotion for children with ADHD compared to controls [To begin with, inconsistent findings refrain us from drawing strong conclusions regarding the degree and type of facial emotion recognition impairments in children with ADHD. A meta-analysis showed that facial emotion recognition abilities in ADHD may depend on the type of emotion studied. In that meta-analysis, controls outperformed children and adults (8–36 years old) with ADHD on facial emotion recognition, albeit effect sizes differed between emotions . For angcontrols –27, and ss d = 0. they wercontrols , 28. ThuFurthermore, the current literature is limited in two aspects. First, studies mainly used high-intensity facial expressions of emotions , 29, 30.The aim of the current study was to investigate child facial emotion recognition abilities in a group of children with (subthreshold) ADHD (referred to as ADHD group) as compared to typically developing peers, using a newly developed facial emotion recognition paradigm , 40. TheThe current study included 83 primary school-aged children (6 to 12 years) with (subthreshold) ADHD (referred to as ADHD group), and 30 typically developing classmates as controls (referred to as controls). Children were included in the ADHD group if they: (a) obtained a score > 90th percentile on the teacher-rated Inattention and/or Hyperactivity/Impulsivity scale of the DSM-based Disruptive Behavior Disorders Rating Scale (DBDRS) , 43; (b)The typically developing control children were classmates of the children assigned to the ADHD group, and were recruited through the teachers that could nominate a classmate of the same age. Controls were required not to attend special education classes and to obtain a score < 80th percentile on the Hyperactivity scale of the teacher-rated SDQ , 47.Children were excluded if they: (a) had an estimated full-scale IQ lower than 70 as assessed with a short form of the Wechsler Intelligence Scale for Children-third edition (WISC-III)  includinSee Table Inattention and hyperactivity/impulsivity. To check whether our allocation to groups was successful, parents and teachers completed the Strengths and Weaknesses of ADHD-symptoms and Normal Behavior (SWAN) rating scale [α = 0.95), and convergent and discriminant validity has been established [ng scale . This raablished .Oppositional behavior. Symptoms of Oppositional Defiant Disorder (ODD) [not at all, 3 = very much). Raw scores may range between 0 and 24, with higher scores indicating more symptoms. The internal consistency is high (α = 0.95), and convergent validity is strong [er (ODD)  were meaer (ODD) , 43 admis strong .Socio-emotional problems. Social and emotional functioning was assessed using both a parent and teacher-rated SDQ [ated SDQ , 52. Thiated SDQ , 53.A modified version of the Morphed Facial Emotion Recognition Task (MFERT) was used to assess facial emotion recognition , 40. PicThe medical ethical committee of the University Medical Center Groningen (UMCG) approved the study procedure. The study was conducted in accordance with the Declaration of Helsinki (2013). Teachers were recruited through school principals, educational consult associations, and outpatient mental health clinics. Teachers, parents, and children older than 11 years, provided consent. Teacher and parent questionnaires were administered via a secured website. Interviews with teachers were administered by the first author (AS). The WISC-III short form and MFERT (in this order) were administered in a quiet room at the child’s school. Standardized instructions were used for the MFERT. In line with the protocol approved by the medical ethical committee, parents of participating children were debriefed about the aim of the study after completing the tasks.t-tests and chi-square test. Missing values were not imputed. Differences in emotion recognition accuracy were tested using a repeated-measures ANOVA, with group  as between-subject factor, and emotion condition  and expression intensity  as within-subject factors. The effects of expression intensity on accuracy were tested using a polynomial trend analysis. When interactions involving emotion condition or expression intensity were significant, post hoc analyses were performed investigating effects of emotion condition and/or expression intensity level. Greenhouse–Geisser correction was applied if the assumption of sphericity was violated. Effect sizes were expressed in terms of Statistical analyses were performed using SPSS IBM, version 25. Differences in demographic characteristics, IQ and ADHD related symptoms and impairment between the ADHD group and controls were assessed using independent samples ectively , 61, ADHExploratory analyses compared children with low and high levels of ODD symptoms in the ADHD group to examine whether comorbid ODD symptoms affected emotion recognition in these children. Children in the ADHD group were allocated to the low and high on ODD group based on median split analysis, according to teacher ratings on the ODD-scale of the DBDRS. The groups were compared on accuracy, committed errors, and RT on accurate trials. We also did a sensitivity analysis, comparing those children in the ADHD group that had not received a clinical diagnosis of ADHD according to parental report to the control group, to check whether (possible) group differences in accuracy held up.Multiple regression analyses examined whether emotion recognition abilities predicted social and emotional problems  within the ADHD group. To measure socio-emotional problems across settings, to enhance reliability, and to reduce error variance, for each of the three SDQ scales, parent and teacher ratings were averaged. To adjust for the effects of sex  and age (months), these variables were entered as predictors in the first step. Percentage correct across all emotion conditions and intensity levels was added in the second step. Alpha level was adjusted for the separate regression analyses on three SDQ scales (0.05/3).G*power to determine the number of subjects needed to test for group differences (ADHD versus control) and group by emotion condition or group by expression intensity level interactions, using repeated measures with 21 measurements . We expected a small to medium group difference, given the inconsistencies in previous studies regarding impairments in emotion recognition of children with ADHD (Cohen’s f = 0.20). Power analysis revealed that we needed a total of 68 children to have sufficient power to detect group differences, and 20 children to detect a group by emotion condition or expression intensity level interactions . To detect a three-way interaction effect, roughly fourfold of the sample size required for a two-way interaction effect is required  [We conducted power analysis using t study) .Group comparisons revealed no group differences in age and IQ. There were more boys in the ADHD group than in the control group  had received a clinical diagnosis of ADHD as established by a child psychiatrist or pediatrician, and that three children (4%) had been diagnosed with a comorbid learning disorder. None of the children had a clinical diagnosis of ODD or were on pharmacological treatment for ADHD. In the control group, one child (1%) had a language disorder, none had a diagnosis of ADHD or ODD.p = 0.051—0.929). For the five outcomes on which Levene’s test was significant, variances were larger in the ADHD group, indicating that the F-statistic is conservative and that violating this assumption for these outcomes will not be problematic [Since unequal sample sizes may affect ANOVA results by violating the assumption of homogeneity of variances, we tested whether both groups had equal variances on all 21 outcomes. Levene’s test showed that variances were similar on 16 out of 21 outcomes  = 4.32, p = 0.040, F = 221.87, p < 0.001, M = 73.87, SD = 1.22) were recognized most accurately, followed by expressions of fear , anger , and sadness  . The effects of emotion condition on accuracy did not differ between the groups, confirmed by a non-significant group by emotion condition interaction on accuracy  = 0.58, p = 0.611, Figure F = 794.57, p < 0.001, F = 5.27, p = 0.024, For expression intensity, the main effect on accuracy was found  = 0.80, p = 0.625, The three-way interaction between group, emotion condition, and expression intensity was not significant  = 361.84, p < 0.001, F = 435.01, p < 0.001, M = 12.79, SD = 4.59), followed by anger , fear  and happiness  . The group by error type interaction was not significant  = 0.27, p = 0.685, Table F = 0.67, p = 0.416, F = 0.81, p = 0.475, Finally, it was tested whether groups differed on RT of correct trials. Repeated measures ANOVA did not reveal an effect of group on RT  = 6.86, p = 0.011, F = 0.47, p = 0.469, F = 3.60, p = 0.063, r = 0.02, p = 0.832), and boys  and girls  did not differ in their accuracy on the MFERT (t(111) = -0.21, p = 0.832).To check whether the observed group differences in the sex distribution affected the results, we matched the ADHD and control group on sex and age. For accuracy, results remained unchanged for the main effect of group (N = 38) and high levels of ODD symptoms  in the ADHD group. Children with low and high levels of ODD symptoms did not differ on accuracy: the main effect of ODD group  = 0.29, p = 0.593, F = 1.60, p = 0.197, F = 0.73, p = 0.516, F = 0.90, p = 0.531, F = 0.886, p = 0.463, F = 5.54, p = 0.021, F = 0.32, p = 0.796, We explored whether comorbid ODD symptoms as assessed with the teacher-rated DBDRS affected the results. Because of the skewed distribution of these scores, median split analyses (median = 6) were used to compare children with low  to the control group (N = 30). Results showed that all findings were essentially replicated with similar effect sizes. The group by intensity interaction remained significant with the largest percentage of variance explained by the quadratic trend  = 5.98, p = 0.016, F = 2.90, p = 0.092, Finally, we explored whether results on accuracy held up when comparing children in the ADHD group of whom parents did not report a clinical diagnosis . Higher overall accuracy scores were associated with less emotional problems. For aggregated parent and teacher ratings of peer problems, a similar pattern emerged: after adjusting for sex and age, accuracy contributed a significant 14% of the variance to peer problems . Higher overall accuracy scores were associated to lower peer problems. Accuracy scores did not significantly contribute to the prediction of ratings of prosocial behavior.We used accuracy of emotion recognition, regardless of emotion and intensity, as a predictor in the regression analyses in the ADHD group. After adjusting for sex and age, accuracy contributed a significant 7% of the variance to the aggregated parent and teacher-rated emotional problems on the SDQ  ADHD, as compared to typically developing controls, using a novel task in which the intensity of different types of emotional expressions was manipulated. Furthermore, we examined whether impairment in emotion recognition accuracy was related to social and emotional problems in the ADHD group. In line with our hypothesis, results showed that the ADHD group performed worse than controls across types and intensities of emotional expressions , with a smaller increase in accuracy with increasing intensities as compared to control children . Despite the small group differences, it appeared that the severity of emotion recognition problems was a predictor of the severity of emotional and peer problems in the ADHD group.In this study, we used a newly developed task to assess facial emotion recognition in children, using four emotions on five intensity levels of child facial emotional expressions. This allowed us to examine subtle differences in facial emotion recognition abilities between children with (subthreshold) ADHD and controls. The main effects of emotion condition and expression intensity found on accuracy support the validity of the task. Finally, we presented facial expressions for a short time increasing its ecological validity .Our study showed that children with (subthreshold) ADHD experience mild problems with facial emotion recognition, regardless of the type of emotion. Group differences were smaller compared to some previous studies in clinical ADHD samples , 21, altThe ADHD group showed a smaller increase in their facial emotion recognition abilities with increasing intensities compared to controls with differences attenuating with high intensities. This indicates that children with (subthreshold) ADHD have particular difficulty in recognizing emotions when expressions are more subtle. In our sensitivity analyses in the sex (and age) matched groups, the group by intensity interaction was no longer significant . It seems unlikely that sex affected the obtained overall results given that sex was not related to accuracy and boys and girls (collapsed across both groups) showed similar task performance. This non-significant result is likely to be explained by a reduction of power in sensitivity analyses.Previous studies suggested that behavior disorder problems  may in fact account for the impairment in facial emotion recognition in children with ADHD , 26, 28.To relate task performance to real-life functioning, we investigated whether impaired facial emotion recognition in the ADHD group was related to social and emotional problems in this group. Indeed, emotion recognition accuracy was inversely related to social and emotional problems in the ADHD group. Apparently, difficulties with the attribution of the correct emotional state to a facial emotional expression are related to peer problems. Children with ADHD are often described as impulsive and intrusive in their social behavior , and ourDespite clear strengths, the current study also has some limitations. First, the sample of children in the ADHD group was recruited through teachers and inclusion criteria were based on teacher measures only. The severity of ADHD symptoms and impairment might therefore be less than in children with a full diagnosis of ADHD. However, teachers reported at least subthreshold levels of ADHD symptoms at school, one-third of the children had a clinical diagnosis of ADHD, and almost the whole sample obtained parent ratings of ADHD in the clinical range, indicating that these children had substantial ADHD symptoms and related impairment. Second, we did not take comorbid autism spectrum disorder (ASD) symptoms into account, although a clinical diagnosis of ASD as indicated by parents was an exclusion criterion for this study. Given the high comorbidity rates for ADHD with ASD  and simiTo conclude, this study used a newly developed task and showed there were case–control differences with small effect sizes in emotion recognition accuracy across emotions for children with (subthreshold) ADHD as compared to controls, with the ADHD group showing a smaller increase in accuracy with increasing emotion intensities. Effects were unrelated to comorbid ODD and sex. Severity of emotion recognition impairments was related to social and emotional problems in children with (subthreshold) ADHD, and may reveal one possible mechanism to explain socio-emotional problems in this group. Future longitudinal studies are needed to examine whether facial emotion recognition impairments play a role in the development of socio-emotional problems in ADHD and whether facial emotion recognition abilities and the proposed resulting social and emotional problems, could be improved by interventions , 75.Supplementary file1 (DOCX 308 kb)Below is the link to the electronic supplementary material.


Recommended treatment for attention deficit hyperactivity disorder (ADHD) includes stimulant medication. While these medicines are effective for most ADHD patients, benefits may wear off, suggesting tolerance. This paper reviews the published literature on tolerance to stimulant medication treatment for ADHD. As there are relatively few studies published, pivotal studies and ADHD treatment guidelines were also reviewed. Research demonstrates physiological changes related to continued stimulant usage in neurons and certain brain regions, suggesting a mechanism for tolerance development. One clinical study showed that 24.7% of patients developed tolerance to stimulants in the time of days to weeks; another showed 2.7% developed tolerance over 10 years. Long term follow-up studies demonstrate that medication response may lessen over longer durations of treatment in a high percentage of patients. Strategies to manage tolerance include switching stimulant medicines, drug holidays, or clinical reassessment. Three cases illustrate challenges with treating patients who develop tolerance to stimulant medication. The paucity of research and lack of guidance to clinicians may contribute to significant under recognition of tolerance to stimulant medication. Further research is required to define clinical tolerance for stimulants in ADHD and to provide guidance on identifying and managing tolerance in clinical practice. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with symptoms of hyperactivity, impulsivity, and/or inattention. The symptoms affect cognitive, academic, behavioral, emotional, and social functioning . A meta-ADHD has been linked to significant decreases in quality of life and functioning. In children and adolescents with ADHD, there are higher risks of school failure, parental and family conflict, social rejection by peers, low self-esteem, and delinquent behaviour . In adolStimulant medications are the most used and considered the most effective medications for treating ADHD children, adolescents and adults with ADHD, and they are recommended as first line medication in clinical treatment guidelines for ADHD ,6,7,8. AA literature review was performed in OVID Medline from 1946 to 2022. Search terms included: attention deficit hyperactivity disorder, methylphenidate, amphetamine, drug tolerance, tolerance. Then, an extensive search of references was performed on the papers found. Pivotal studies  study and its longitudinal follow-up papers) and ADHD treatment guidelines were reviewed. Inclusion criteria for this review included: child, adolescent, or adult ADHD; English language; basic science research on the physiological impact of stimulant medications on the brain and/or neurons; specific research on tolerance to stimulant medications or related papers; treatment guidelines for the treatment of ADHD. This review yielded 23 papers. Three retrospective case reports describe the clinical management of tolerance to stimulants. These clinical cases were patients who developed early tolerance to stimulant medicine and who had complete or substantial loss of clinical benefit from stimulant medicine. They were drawn from a suburban specialty ADHD clinic that assesses and treats ADHD across the lifespan.The literature review will be divided into the sections of physiological studies on tolerance, clinical research, and a review of clinical ADHD treatment guidelines. Then, case reports will be shared.From a physiological perspective, chronic use of medication can cause brain changes. Animal models demonstrate that chronic treatment with methylphenidate (MPH) in rodents yields an attenuation of dopamine release probably due to an upregulation of the dopamine transporter or an increase in autoreceptor sensitivity .Research also shows acute tachyphylaxis with MPH. Tachyphylaxis is defined as a rapid decrease in efficacy, often related to a rapid depletion of neurotransmitters . Acute tp < 0.01) in striatal dopamine transporter availability in the caudate, putamen, and ventral striatum [In a PET study of medication naïve adults with ADHD taking MPH for 12 months (compared with controls), it was shown that there was a significant increase  required more than 60 mg of MPH per day, which is an off-label high dose of this medication. Of the 68 high-dose patients, 41 (60%) developed tolerance ; that is 24.7% of the original sample (41/166 patients). The authors note that tolerance only developed in patients taking higher-dose MPH. Tolerance either developed within a few days or it could have taken more than a year. The authors noted that if patients developed tolerance to MPH they were switched to dextroamphetamine. If the substitute was less effective than MPH, the latter would be tried again in about one month, and in many cases, tolerance disappeared after one month [A meta-analysis and a meta-regression were completed to assess the duration of treatment with pharmacological treatment for ADHD and efficacy . They inIn a study of longer-term response to methylphenidate treatment, researchers monitored the behavioural benefits of MPH in patients who were treated with medication from 3 years to 10 years. When the dose of MPH was adjusted for growth, the medication remained effective for the majority of the patients for 10 years. Only 3 of 108 patients (2.7%) lost the therapeutic response without an evident explanation other than the possibility of tolerance. The data showed that successful long-term treatment with MPH did not require increasing the dose beyond the need to adjust for body growth. The authors acknowledge that they only looked at children who were good responders to MPH, and if they had lost their response to MPH prior to 3 years of treatment, they would not have been included in this study .In a study of 47 children with ADHD and reading disorder, researchers looked at different doses of MPH  twice daily for 6 months. They found that the 0.7 mg/kg group had significant improvements in teacher and parent rated hyperactive behaviours, as well as improved short-term memory and associative learning tasks. The teachers noted an increase in hyperactivity during the last three months of treatment, and this was not explained by MPH plasma levels. The cause of this change was suspected to be tolerance, though the authors acknowledge that it could possibly relate to situational issues, particularly because there was a  worsening in the placebo group as well in the last three months of the study .In a meta-analysis and a meta-regression study of pharmacotherapy in adults with ADHD, researchers analyzed data from 44 studies with 9952 patients. The range of duration of the studies was 4–26 weeks. The analysis showed that the longer the study duration the smaller the efficacy of the pharmacological treatment for reducing ADHD symptoms. This may suggest chronic tolerance to the medication in adults treated for up to 26 weeks .Two randomized withdrawal treatment studies have been reported, one with lisdexamfetamine (LDX)  and one In the pivotal National Institutes of Mental Health funded multimodal treatment study (MTA), 579 children with combined-type ADHD were treated for 14 months in a randomized study design that compared medication management, behavioural therapy, combination treatment, and community control . There wSibley et al., analyzed the course of ADHD during the naturalistic follow-up of the MTA study, from each of the assessments from 2–16 years. They found that approximately 30% of children with ADHD experienced full remission at some point during the follow-up period; however, a majority of them (60%) experienced recurrence of ADHD after the initial period of remission. Only 9.1% of the sample demonstrated recovery by study endpoint, and only 10.8% demonstrated stable ADHD persistence across the study time periods. Overall, 63.8% of participants with ADHD had fluctuating periods of remission and recurrence over time . The natTwo research papers addressing clinical treatment of ADHD were relevant, one on ADHD drug holidays  and the These studies are summarized in Published ADHD treatment guidelines were reviewed, looking for direction to clinicians around tolerance to stimulant medication. The following ADHD guidelines were reviewed: American (child and adolescent ADHD) , EuropeaA was seen in consultation in April 2020 at the age of 38 years old. She had been diagnosed with ADHD as a child and briefly took MPH immediate release but did not want to continue it. She restarted ADHD medication in the recent past and was referred for assessment. She was taking LDX 40 mg daily at the time of consultation. Her diagnoses were: ADHD combined presentation, binge eating disorder, cannabis use disorder, past history of substance use disorders (cocaine and ecstasy) in remission for 10 years, polycystic ovarian syndrome, and prediabetes. When she started LDX, it was helpful, but the benefits were wearing off early in the day after several weeks. At the initial consultation, the dose of LDX was increased by adding a midday dose of LDX 10 mg. The patient also started cognitive behaviour therapy (CBT) for adult ADHD. A pattern developed that A would have benefit to increased doses of LDX, but the benefits disappeared after days or weeks, and the medicine would wear off earlier and earlier in the day. With discussions of the safety of “off-label” dosing, and with blood pressure monitoring, A was doing better with LDX 110 mg daily . After several months, the LDX stopped working completely.A was switched to OROS MPH, with a rapid upward titration of dosing. She reached a dose of OROS MPH 117 mg daily, with OROS MPH 72 mg in the morning and 45 mg midday. This proved somewhat helpful, though not as helpful as the LDX. The benefits started to wear off, and after 4 months she was not experiencing benefit from the medication anymore. She was switched back to LDX.While working with A over time, a pattern was established: she did better with LDX than she did with OROS MPH, it provided better symptom control overall for her ADHD and functioning. When she took OROS MPH, she wanted to minimize the time she took it for. Initially, she would take it for 4 weeks in an attempt to reset her tolerance to LDX, and it was successful. Since it did not work as well for her ADHD, we tried lowering the duration of OROS MPH as a break from LDX. When A tried it for only 7 days, the tolerance to LDX did not reset, and it was eventually discovered that she required at least 10 days of MPH to reset her tolerance to LDX. Furthermore, while initially A took LDX for around 2–3 months and waited for its benefits to drop off before taking MPH to reset the tolerance, it was decided to proactively switch the medicine earlier to avoid the loss of benefit from the LDX and to maintain more stability.After approximately 1 year of adjusting and experimenting, A found that taking LDX for 5 weeks followed by MPH for 10 days provided the most stability for her and allows her to function best. Her final dosing is: LDX 110 mg daily ; OROS MPH 117 mg od . She continues with CBT for ADHD, has lowered her cannabis use, and started working again after a long hiatus of unemployment.B is a 17-year-old man who was diagnosed with ADHD combined presentation, mild oppositional defiant disorder, and adjustment disorder with anxiety. He had taken OROS MPH 72 mg daily and, while it worked well for him, it stopped working completely after 2 months. He tried other formulations of long-acting MPH with no success. He tried amphetamine-based medicines, including LDX and mixed amphetamine salts extended release (MAS XR). LDX did not provide symptom relief and contributed to anxiety symptoms. MAS XR worked for one week and then the benefits wore off.B was tried on several other ADHD medications, including: guanfacine XR (GXR), up to 3 mg daily, in combination with stimulant medicines. He did not find that it helped at all, and no benefits were noted. He tried MPH Immediate release and, while it was helpful, the benefits disappeared after 2 weeks. He tried dextroamphetamine immediate release and, while it was helpful, the benefits wore off after 1 week. He tried atomoxetine (ATX) 60 mg daily (1 mg/kg/day) and there were no benefits plus significant nausea side effects. He tried bupropion XL 300 mg daily (as an off-label treatment for ADHD) and there were no benefits for focus, and he had significant insomnia. He tried modafinil 100 mg daily (as an off-label treatment for ADHD) and it did not help focus, but worsened insomnia.B stopped all ADHD medication and also stopped his post-secondary education/training. His anxiety got worse, and he was treated with an SSRI, sertraline at 150 mg daily, and it was somewhat helpful for his anxiety symptoms, though his ADHD remained untreated.C is a 10-year-old girl who was diagnosed with ADHD combined presentation by her pediatrician. She has no comorbid diagnoses. Her father has ADHD, both grandfathers have alcohol use disorders, and one also has bipolar disorder. There are no significant stressors in the family, apart from the recent global pandemic. She was initially prescribed LDX and it worked well for her symptoms. Within weeks, the medicine wore off earlier in the day, until it stopped working by noon. When it wore off, she experienced significant symptoms, including worsened focus, hyperactivity, anxiety, and emotional dysregulation. Immediate release dextroamphetamine (Dex IR) was added midday to extend the benefits of LDX with good effect. When this combination of medicines’ benefits wore off after several weeks, GXR was added and brought up to 3 mg daily. The GXR helped the stimulant medicines to last longer in the day and C did not experience significant negative symptoms when the medicine was wearing off.Eventually, the benefits of LDX, Dex IR, and GXR were not significant, i.e., she had become tolerant. C was put onto OROS MPH and it worked well initially, but then the medicine was wearing off earlier in the day and the dose had to be increased. Eventually, she reached OROS MPH 72 mg daily, with MPH IR 7.5 mg midday, and she continued on GXR 3 mg daily. C did well with this for about 3 months and then the medicine was no longer helping.She then switched back to LDX with GXR. When she first switched over to LDX, it lasted long enough and she did not need a midday dose of DEX IR. Then, the pattern repeated. She has been on LDX, Dex IR, and GXR for about 5 months and she has become tolerant; she will soon switch back to the MPH medications.ADHD is a condition that starts in childhood and lasts into adulthood for most patients. There are significant impairments related to ADHD. Standard treatment includes stimulant medication, among other possible medicines and psychotherapy. While stimulant medicines can work very well for ADHD, there is a concern about tolerance developing to these medications.Physiological research demonstrates the biological adaptation to medication. With stimulant medication, there are changes in neurons and brain regions that can explain the mechanism of pharmacodynamic tolerance. The studies reviewed document that, although their studies demonstrated cellular changes, the stimulant medicines continued to work clinically.Clinicians have observed patients who have lost benefits to stimulant medicine over time , though it can be hard to establish whether this is tolerance to the medicine, other clinical factors such as poor adherence to treatment, comorbid conditions, or the natural course of ADHD over time. The 16-year follow-up of the MTA study demonstrates that over time, ADHD may worsen or improve, related to the natural course of ADHD . As suchA 2002 paper suggested that tolerance to stimulant medicine was common, occurring in 24.7% of randomly selected charts, and, interestingly, all the cases of tolerance were in patients who were on doses higher than 60 mg MPH per day . In a stWhile Ross et al.,  discuss There is no clear definition of tolerance to stimulant medication. These different studies suggest that clinicians should consider “early tolerance” for the clinical situation of losing the benefits of stimulant within days or weeks, and a more gradual or “late tolerance” for the clinical situation of losing the benefit of stimulant medicine over the course of months or years.Furthermore, the extent of clinical benefit lost related to tolerance is not always documented clearly in the research. Some studies refer to complete loss of benefit to the medication, and other studies refer to a reduction of clinical benefit obtained from the medication. To assist with the clinical care of patients, future research could consider documenting whether there is “partial tolerance”, i.e., some reduction in ADHD symptom control, or “complete tolerance”, referring to a substantial or complete loss of benefits of the medicine.Published ADHD treatment guidelines are helpful summaries of the research and its clinical application to treat patients with ADHD. Unfortunately, they do not provide guidance to clinicians around defining tolerance to stimulant medication, how to identify tolerance, nor how to clinically approach tolerance when it occurs.When patients experience tolerance to stimulant medicines, the research suggests the following strategies: medication holidays to reset the tolerance ,25; switThree clinical cases reviewed demonstrate patients who clinically develop tolerance to stimulant medicines in a short period of time, i.e., “early tolerance”. They also experienced “complete tolerance”. In two of the cases, clinical care has been successful by switching patients from one stimulant family  to the other , similar to the recommendation from Ross et al., . ClinicaBased on this review, the research suggests that there is a small percentage of patients with ADHD who develop “early tolerance” to stimulant medicines and a potentially larger percentage have a more gradual or “late tolerance” over years. Similarly, it seems that there are relatively few patients with ADHD who develop “complete tolerance” (complete loss of benefit of the medicine) and potentially a larger percentage who have “partial tolerance” . Strategies to combat stimulant tolerance include: switching classes of stimulants ; taking medication holidays to reset the tolerance; using other treatments, such as psychotherapy, non-stimulant medications, and reassessing clinically .There is a significant disparity between the reported rates of tolerance in the published literature (anywhere from 2.7% of patients over a 10-year study to 66% of children at 3 years to 9952 adults with ADHD losing some benefit of the medicine over a period of 26 weeks). There are demonstrated physiological mechanisms that underlie the biological basis of tolerance. Since there is a paucity of research on tolerance to stimulants, no clinical guidance in published ADHD treatment guidelines on identifying and managing tolerance to stimulant medication, and no clear definition of tolerance to stimulants, it is likely that tolerance to stimulant medicine is significantly under-recognized and under-reported. This is a significant clinical issue with a biological basis that urgently requires more research and clinical guidance. As the rate of stimulant usage is reported to have doubled in the United States of America between 2006 and 2016 [Furthermore, tolerance to psychopharmacology is not unique to ADHD. With mood disorders, studies document that patients treated with lithium for bipolar disorder may experience tolerance or discontinuation-induced refractoriness . TreatmeTreatment of ADHD with stimulant medicine is generally effective and can help for many years. Research shows that some patients develop an “early tolerance” to these medicines, meaning they have an initial good response but the benefits wear off within days or weeks; some patients may develop more gradual or “late tolerance” to stimulants, where the benefits are lost over months or years of treatment; some patients also develop “complete tolerance” with a substantial or complete loss of clinical benefit to stimulants; some patients may develop “partial tolerance” with a partial loss of clinical benefit. There is insufficient research to clearly define clinical tolerance to stimulant medication in ADHD, and there are suggestions in the literature on strategies that may help, such as switching classes of stimulants (from MPH to AMPH and vice versa) to reset the tolerance or taking medication holidays and reassessing clinically for comorbid conditions or other clinical factors which may affect treatment response. There is a clear biological basis for stimulant medication tolerance, and the lack of sufficient research and guidelines may suppress recognition of this significant clinical issue and negatively impact patient outcomes. More research is needed and clinical guidelines should be updated to provide more guidance to clinicians on how to identify and manage tolerance to stimulant medication.


New research shows that the prevalence of neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD), is increased in children and adolescents as well as in adults with chronic pain, compared to those without chronic pain. Children and adolescents with ADHD also have an increased incidence of various physical conditions associated with pain, and they more frequently suffer from inflammatory diseases. Moreover, parents of children with ADHD can often suffer from pain conditions. These epidemiological and clinical observations form the scientific basis of our study, which aims to map the relationships between ADHD, altered pain experiences/central sensitization, and inflammation in children and adolescents. We will investigate the presence of central sensitization in children and adolescents with newly diagnosed ADHD and compare it with those who have not been diagnosed with ADHD. Participants  will complete surveys about their somatic health, pain experience, and quality of life. Biological samples  will be collected, aiming to utilize proteome and metabolome data to discover disease mechanisms and to predict, prevent and treat them. The results from our investigation should enable an expanded understanding of the pathophysiology behind both ADHD and pain/central sensitization. Presently, there are no established protocols for addressing psychiatric symptoms when examining patients with pain conditions in a somatic care setting, nor is there any knowledge of offering patients with ADHD or other neurodevelopmental disorders adapted treatments for pain conditions. Our results, therefore, can contribute to the development of new treatment strategies for pathological pain conditions in children and adolescents with ADHD. They may also increase awareness about and provide opportunities for the treatment of attention and impulse control problems in children and adolescents with pain syndromes. Attention-deficit/hyperactivity disorder (ADHD) is recognized by its core symptoms—inattention, hyperactivity, and impulsivity. There are three recognized subtypes of ADHD: predominantly inattentive, predominantly hyperactive/impulsive, and the combination of both. The lifetime prevalence of ADHD is approximately 5% .ADHD is a neurodevelopmental disorder; it has a neurobiological background that affects children’s behavior and functioning during early development . The undNew research shows that the prevalence of neurodevelopmental disorders, such as ADHD, is increased in children and adolescents with chronic pain . ChildreToday’s pain research highlights the concept of “central sensitization” (CS), or the brain processing both internal and external stimuli with increased sensitivity . Our hypMultiple lines of evidence  show that the activation of immune system molecules and pathways can contribute to and play a significant role in the pathogenesis of psychiatric disorders –21. SomeEpidemiological studies, including meta-analyses, have revealed that patients with ADHD are more likely to suffer from asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis—all well-known inflammatory conditions—than control subjects. Associations between ADHD and systemic autoimmune diseases  have also been shown , 26.Assuming inflammation plays a key role in the pathogenesis of psychiatric disorders, anti-inflammatory treatments may represent a promising therapeutic intervention.In the present project, we aim to 1) gather clinical data regarding the association between ADHD (with or without other co-occurring conditions) and pain and 2) suggest neuroinflammation as a possible link between altered pain perception and ADHD (and co-occurring conditions) and, therefore, that targeting neuroinflammation may be a promising therapy . The PaiThe clinical portion of the project aims to investigate subjective pain experiences and pain perceptions in children and adolescents with newly diagnosed ADHD while monitoring their inflammatory biological markers. More specifically, we propose to:Investigate whether subjective pain experiences (by self-reported and parent-reported inventories) and pain perceptions (CS detected by sensitivity to pressure) differ between groups of children with ADHD only, with ADHD+autism spectrum disorder (ASD), with ADHD+other co-occurring psychiatric conditions, and without ADHD.Determine whether levels of inflammatory markers  differ between the aforementioned groups.Investigate functional impairment and quality of life in children and adolescents with and without ADHD and with and without co-occurring psychiatric conditions in correlation with pain experience and perception.https://www.spirit-statement.org/). Participants will be recruited to the clinical group from child and adolescent psychiatric (CAP) clinics in the Västra Götaland region of Sweden and to the comparison group from schools in the Västra Götaland region. Inclusion criteria for the clinical group include 1) fluently Swedish-speaking child/adolescent (age 7–18) and at least one parent and 2) a child/adolescent ADHD diagnosis within the previous 12 months. We chose to require a biological parent (not a guardian) in the study to ensure the genetic relationship between the child/adolescent and the adult—this will allow us to analyze the adults’ responses about their own pain experiences  in correlation with their children’s responses, assuming a shared genetic component behind these responses. Exclusion criteria for the clinical group include intellectual disabilities, psychotic disorders, bipolar disorder, anorexia nervosa, bulimia nervosa, substance use disorder, and suicidal tendencies. Inclusion criteria for the comparison group include fluently Swedish-speaking child/adolescent (age 7–18) and at least one parent. Exclusion criteria for the comparison group include all aforementioned exclusion criteria for the clinical group plus an ADHD diagnosis.The study protocol was developed in accordance with the SPIRIT  guidelines and checklist . The research nurse will examine the participants; measure pulse, blood pressure, weight, and height; collect biological  samples; provide them with the questionnaires; and assist them if help is required. Finally, the physiotherapist will identify signs of altered pain processing . During this examination of the participant, the parent will complete assigned questionnaires. The whole meeting will take approximately 60 minutes.Parents of children and adolescents (15 years and older) who agree to participate in the study will send their written consent to a research nurse, who will pseudo-anonymize the patients in the clinical and control groups by assigning a code to each child/adolescent. For the clinical group, the research nurse will collect information about each patient’s medical record (concerning psychiatric diagnoses and drug treatment) from the CAP’s medical record system. For both groups, the research nurse will arrange a meeting at a CAP clinic in the Västra Götaland region for the participant, a parent, and a physiotherapist connected to the project , . The forPediatric Quality of Life Inventory–Family Impact ModuleThe  for parents is a self-assessment of parents’ and families’ feelings. It is a 36-question inventory divided into eight scales: physical, emotional, social, and cognitive function and communication, worry, daily activities, and family relationships [ionships . Higher ionships . The Sweionships .Pediatric Quality of Life InventoryThe  [nventory  for parenventory . It is anventory .Central Sensitization InventoryThe  (CSI) [ry (CSI)  is used ry (CSI) .Central Sensitization Inventory for Children and AdolescentsThe  is an adapted version of the CSI for self-assessment of central sensitization in teens and children [children . The valsomatic health formA  is used to identify any physical illnesses in a child/adolescent as reported by the parents. This questionnaire has shown high test-retest reliability [iability  and has iability .Lübeck Pain Screening QuestionnaireThe  is used for children/adolescents to estimate the incidence, type, degree, and frequency of any pain [any pain  and has any pain .Pediatric Pain QuestionnaireThe  [www.pedsql.org.ionnaire  assessesionnaire . This in2 rubber tip and an application rate of 1 kg/s will be used. The child/adolescent will report when the pressure becomes uncomfortable.Pain sensitivity will be assessed by measuring each child/adolescent’s pressure pain thresholds at the trapezius muscle, deltoid muscle, lower back, and tibialis anterior muscle on her/his dominant side, distributing the measuring points on the upper and lower quadrants and axially. A handheld pressure algometer  with a 1 cmConditional pain modulation will be used to measure endogenous pain inhibition. The subject’s perception of the pain intensity of a test stimulus will be measured before and after the addition of a conditioning stimulus. In this study, we will use cold as a conditioning stimulus and pressure as a test stimulus. The conditioning stimulus will be applied as follows: the participant will be asked to place her/his non-dominant hand in a cold pressor unit containing water maintained at a temperature of 10 ± 1°C , 43. TheThe measurement of central sensitization is not expected to pose any particular risks to the participants or their parents. However, it is important to consider that the pressure pain measurement may cause mild, momentary discomfort; some participants may experience this as painful.Based on previous evidence regarding pain modulation theories, we expect that an individual without signs of CS will respond to the conditioning stimulus (cold) with reduced sensitivity to the test stimulus (pressure). In contrast, an individual with signs of CS will have an unchanged or increased sensitivity to the test stimulus.saliva sampleA  will be collected from each patient according to the protocol at the clinic.Despite some differences between the protein and autoantibody levels in saliva versus blood serum, saliva is an easily accessible biological fluid that partly reflects the circulating bodily fluids. Therefore, saliva has both scientific and clinical potential , 45.Collecting patients’ saliva samples as part of our study protocol allows for molecular profiles  to be established and used as variables. These variables will serve as valuable additions to the clinical data and make it possible to stratify patients into different groups according to their genetic or biological risk scores. Inflammatory protein and metabolite panels can be assessed, as can known genetic variants involved in autoimmune disorders, chronic inflammation, and pain. We will analyze RNA, and DNA from the saliva microbiome and the host cells within the saliva fluid by microarray and next-generation sequencing (NGS). To analyze the metabolites involved in inflammation, state-of-the-art nuclear magnetic resonance (NMR) spectroscopy will be used. Inflammatory protein biomarkers  will be investigated via antibody-based multiplex protein panels. Selected inflammatory markers  will also be analyzed individually via enzyme-linked immunosorbent assays in the CAP clinic’s laboratory. Known autoantibodies against proteins in the digestive tract and nervous system that are involved in pain perception will be investigated to rule out pain that may result from autoimmune reactions  . Excludistool sampleA  collected at home 1–2 days before the visit will be submitted at the visit. When the intestine is inflamed, calprotectin is released by neutrophils. Calprotectin is not specific, but its increased level in fecal excretions is seen in conjunction with different diseases. Therefore, we also want to measure calprotectin as a marker for inflammation, and we will examine the correlations between calprotectin and other biomarkers and symptoms using information about the child/adolescent’s intestinal flora profile as measured by 16S rRNA sequencing.Data will be collected through self-reports from children and parents, from the pressure pain measurements  from children, from the saliva and stool samples (for inflammatory markers), and from the medical record system regarding diagnoses and medications for the clinical group. All data will be coded.The effect size for the measurement method of central sensitization is not yet known. Calculations are ongoing in a study at Queen Silvia Children’s Hospital, but the results are not yet clear. Therefore, we have estimated the effect size as small in the following power calculation and made a theoretical calculation of the population size. When we used power analysis for “MANOVA special effects and interactions” with an effect size of 0.07 and a power of 0.80, it was suggested that the number of participants should be 252 for eight groups.These eight groups are: 1) comparison group boys, 2) comparison group girls, 3) clinical group boys with only ADHD, 4) clinical group girls with only ADHD, 5) clinical group boys with ADHD+ASD, 6) clinical group girls with ADHD+ASD, 7) clinical group boys with ADHD+other co-occurring psychiatric conditions, and 8) clinical group girls with ADHD+other co-occurring psychiatric conditions. Other co-occurring psychiatric conditions will include anxiety disorder, depression, stress disorder (including posttraumatic stress disorder), and behavioral disorders .In the power calculation, four predictors  and four response variables  were used. This suggests that the study requires at least 32 children per group—at least 64 children (32 boys and 32 girls) for the comparison group, 64 children with only ADHD, 64 with ADHD+ASD, and 64 with ADHD+other co-occurring psychiatric conditions.In summary, we will include 192 children in the clinical group and 64 children in the comparison group as targets for data collection.The differences in variance between the clinical groups and the comparison group—with respect to CS results, the prevalence and intensity of pain, and quality of life (as reported by children and parents)—will be analyzed using multivariate analysis of variance. The level of parental self-rated CS will be correlated with that reported by and tested in their own child using Spearman’s correlation. The child’s measured level of CS will be correlated by multiple regression with the following independent variables/predictors: age, gender, presence (and type) or absence of psychiatric diagnoses, self-rated CS, parent-rated CS in the child, parent self-rated CS, self-rated pain sensitivity, parent-rated pain sensitivity in the child, and levels of inflammatory markers in saliva and stool samples.Fig 2), we will test a moderated mediation hypothesis between inflammation and quality of life; pain (CS) and ADHD (psychiatric conditions) will be tested as mediators and each other’s moderators .The association between the child-reported quality of life and the parent-reported quality of life of the child and the family will be analyzed via regression models. Using conditional process analyses  . The research nurse will verbally describe the study’s purpose, aim, procedure, and methods to each participant. A written form will also provide more detailed information about the background and purpose of the research, risks/benefits of participating, research structure, compensation for participation, and information about the management of project data. It will be clear that the study is voluntary and anonymous and that the data collected will only be used for the study. The participants will have the opportunity to ask questions about the project and about how their information will be used.The instruments used in this study will be established psychiatric or physiological measures, each previously used in child and adolescent populations. They are not considered to pose any risk, either during the time of the study or in the long term.During data collection, the clinics will follow their standardized patient safety and data security regulations. This category of data is defined as sensitive personal data according to the EU Data Protection Regulation (GDPR). Clinics participating in the study are responsible for obtaining informed written consent from the participants and then pseudonymizing (coding) sensitive personal data so that the patients’ identities are protected in an appropriate manner. Both paper-and-pen and electronic information  will be coded. Biological material will also be marked with the appropriate participant’s code; no personal information will be included. All samples will be destroyed upon the completion of the project. No follow-up of the participants is planned or necessary. Code keys will be available only at the clinics during data collection and will be destroyed after the coded data is transferred to University West, where data analyses will be performed. The research material will only be processed and shared with other researchers in its deidentified form.P = 0.032). A similar tendency was found in boys . These study results are now under peer review prior to publication [P = 0.043).Our research group has performed a pilot study  to map tlication . The subA recent study concluded that saliva can be used to monitor ADHD status with regard to biomarkers that indicate the hypothalamus–pituitary–adrenal axis and sympathetic activity . FurtherOur French preclinical partner in the PiPCo study has demonstrated that their animal model of ADHD, mice with 6-hydroxydopamine (6-OH) lesions, has good constructive validity to reproduce both primary symptoms of ADHD and secondary symptoms  . The aniOur Spanish preclinical partner in the PiPCo study investigates inflammatory responses and changes in the intracellular signaling pathways in ADHD mice. They also tested a natural anti-inflammatory drug, “abscisic acid” (ABA), found in high concentrations in avocado and citrus fruits, among others. In previous animal studies, they showed that ABA administration prevented the pathological increase of inflammatory markers in the brain and that its effect resulted in improved cognitive capacity in different neurological animal models. This suggests that ABA is a potential candidate for treating inflammatory conditions of various etiologies to prevent declines in cognitive function.The study has pragmatic and clear needs-oriented significance regarding the care and treatment of children and adolescents with ADHD and pain. The care of this patient group is currently undeveloped, and the existing level of knowledge is low. There are great socioeconomic gains to be made by streamlining and improving the care of this patient group. Studies examining the economic impact of ADHD in children/adolescents found annual national ADHD costs ranging between 1.041 and 1.529 billion euros, with ADHD-related costs of 9,860–14,483 euros per patient . Here, wThe study also has a heavier scientific ambition—to contribute to the development of knowledge regarding the brain’s biological processes and mechanisms that drive and generate disability and suffering in the form of psychiatric symptoms and pain. The connections between neuroinflammation and psychiatric disorders are currently being studied intensively. Several recent studies imply a link between activation of the immune system and psychiatric symptoms , 21–24. We wish to present- based in reviewer criticism—a culture specific explanation, why we use the expression in this study “individuals with ADHD” and not “ADHD individuals”. In Sweden within clinics and ethical applications it is encouraged to use the expression “individuals with a …diagnose”, arguing that the disorder/diagnose does not identify/define a person. In our study population, only part of childhood ADHD diagnosis will persist into adulthood, and if it is correctly treated it should not leave any psychiatric or somatic/pain residues to adult hood.We will likely not solve the whole puzzle of how inflammation and pain perception can affect mood and behavior, but we can identify pieces that, until today, have been undefined. By focusing on children and young individuals with ADHD and their special needs in connection with pain and healthcare encounters, we can assist this group in receiving the necessary attention. Perhaps, to some extent, we can also improve healthcare’s ability to manage and treat this population.The results will enable an improved understanding of the pathophysiology behind both ADHD and pain/central sensitization and may contribute to the development of new treatment strategies for pathological pain conditions in children and adolescents with ADHD. This project represents an important step in increasing awareness and providing opportunities for the treatment of attention and impulse control problems in children and adolescents with pain syndromes.Because of the serious societal impact of this condition, it is crucial to raise awareness about the associations that exist between ADHD and other health conditions in order to enhance recognition and improve treatment.The associations between pathological pain and neuropsychiatric diagnoses have rarely been studied in children and adolescents. We aim to contribute to an increased understanding of and attentiveness toward the specific needs of this patient group in healthcare encounters. Pain is common in healthcare settings but assessing and treating pain based on individual adaptations has not been commonly practiced. If our study confirms that children and adolescents with ADHD experience pain differently than those without, this knowledge is to be implemented in healthcare, both regarding the specialized care of chronic/pathological pain and ADHD and in everyday healthcare of children and young people with ADHD . Furthermore, if our study can point toward certain inflammatory processes that might underlie pain perception and ADHD, new anti-inflammatory or biological treatment opportunities may be possible.


Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impairing symptoms of inattention and/or hyperactivity/impulsivity. Although Emotional Dysregulation (ED) is not current criteria for ADHD, several clinical, imaging and genetic studies have been suggesting its inclusion. ED seems to impair social and occupational capacities, leading to poor quality life. In this regard, managing this situation is fundamental.ED in ADHD review and its management, including pharmacological and nonpharmacological approaches.Non-systematic review through literature using databases as Pubmed and UpToDate. Keywords used: Attention-Deficit/Hyperactivity Disorder, Emotional Dysregulation, management, pharmacotherapy.Literature refers to ADHD drugs, such as psychostimulants and atomoxetine, as the first line managing ED. However, some studies demonstrated that ADHD drugs have lower efficacy while treating emotional symptoms, when compared to attention or hyperactivity/impulsivity symptom control. Other medications, such as antidepressants or mood stabilizers, are not considered due to low efficacy and side effects . Regarding non pharmacological approaches, there have been results with cognitive behavioral treatment, and management techniques for anger, frustration and communication skills.Although the majority of studies demonstrate psychostimulants and atomoxetine role, there is an important lack of information regarding management of ADHD emotional dysregulation. It is a multifactorial condition, and, as such, non pharmacological and pharmacological management are needed to address this issue. More research is necessary, in order to improve patients’ quality of life.No significant relationships.