Comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and mood disorders is common. Alterations of the cerebellum and frontal regions have been reported in neuro-imaging studies of ADHD and major depression.99mTc-HMPAO SPECT. Controls for 99mTc-HMPAO SPECT were 16 healthy females. SPECT was analyzed by both statistical parametric mapping (SPM2) and the computerized brain atlas (CBA). Discriminant analysis was performed on the volumes of interest generated by the CBA, and on the scores from rating scales with the highest group differences.Thirty chronically depressed adult females of whom 16 had scores below, and 14 scores above, cut-offs on the 25-items Wender Utah Retrospective Scale (WURS-25) and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) were divided into subgroups designated "Depression" and "Depression + ADHD", respectively. Twenty-one of the patients had some audiological symptom, tinnitus and/or hearing impairment. The patients were investigated with other rating scales and The mean score of a depression rating scale (MADRS-S) was significantly lower in the "Depression" subgroup compared to in the "Depression + ADHD" subgroup. There was significantly decreased tracer uptake within the bilateral cerebellum at both SPM and CBA in the "Depression + ADHD" subgroup compared to in the controls. No decrease of cerebellar tracer uptake was observed in "Depression". Significantly increased tracer uptake was found at SPM within some bilateral frontal regions  in the "Depression + ADHD" subgroup compared to in "Depression". An accuracy of 100% was obtained for the discrimination between the patient groups when thalamic uptake was used in the analysis along with scores from Socialization and Impulsivity scales.99mTc-HMPAO uptake in "Depression + ADHD" compared to in "Depression" indicate a difference between these subgroups. 99mTc-HMPAO uptake mechanisms are discussed.The findings confirm the previous observation of a cerebellar involvement in ADHD. Higher bilateral frontal  The persistence of Attention Deficit Hyperactivity Disorder (ADHD), previously thought of as a self-limiting condition that rarely requires treatment in adult life, has only come into focus of widespread clinical attention and research in the last decade. In 1998, it was suggested that ADHD may be "the most common chronic undiagnosed psychiatric disorder in adults" . Higher High heritability of ADHD irrespective of whether continuum or categorical approaches were used, or if different cut-off criteria were applied, was reported in a large twin study . The reqSimilarities between adult and childhood ADHD such as impaired cerebello--striato-frontal networks have been suggested . In a stSingle Photon Emission Computed Tomography (SPECT) is the mostly available functional neuro-imaging method. SPECT systems detect γ-rays emitted by injected radioactive substances.99mTc-d,l-hexamethylpropylene amine oxime (99mTc-HMPAO) used at SPECT is generally considered to reflect cerebral blood flow (CBF). However, discrepancies in the same brains have been reported between the uptake of 99mTc-HMPAO and other SPECT perfusion tracers, and with PET results , was usFive patients with high WURS-25 and WRAADDS scores, all adult daughters with normal hearing of hearing impaired mothers, were thoroughly investigated with a neuropsychological test battery at a specialized neuropsychiatric unit. The investigation included clinical interviews , questionnaires, rating scales, and neuropsychological tests including the computerized visual Test of Variables of Attention .Sixteen healthy adult females , all with normal MADRS scores, served as controls. They were selected from a group of individuals who had undergone SPECT with the intention that they would be utilised as a normal control group for SPECT analyses . The stu99mTc-HMPAO  was injected after 30 minutes rest in a quiet dim lighted room. Examinations started between 45 and 60 minutes after tracer injection. The projection data were acquired for 30 seconds per projection at 90 equal angles of a complete revolution. Between 8 and 10 million total counts were acquired.Brain imaging using SPECT was performed using a three-headed Gamma Camera  equipped with low-energy ultrahigh-resolution (LEUHR) collimators. The intrinsic spatial resolution of the camera was 8 mm at Full Width Half Maximum. 3.Before back-projection we pre-processed the one-dimensional data with a Hamming smoothing filter with a cut-off frequency of 2.25 cycles/cm. Then SPECT images were reconstructed by filtered back projection algorithm using a ramp filter with a cut-off frequency of 0.6 cycles/cm. Attenuation correction was based on a four-point ellipse . No scatSPECT raw images were transformed into the analyze format by XMedCon package. Data were analyzed with SPM2  implemented in Matlab 6.5.1. Images of relative tracer distribution were spatially normalized into the stereotactic Montreal Neurological Institute (MNI) space, a predefined SPECT template available in SPM2 (voxel size 2 × 2 × 2 mm), using a 16-parameter affine (non-linear) transformation. Because this template doesn't completely match the Talairach brain, it was necessary to correct the SPM{t} coordinates. This was achieved using the subroutine implemented by Matthew Brett . BAs wheAfter normalization, images were smoothed with a Gaussian filter of 12 mm (FWHM) to account for individual gyral differences and brain anatomy and to increase the signal-to-noise ratio. Images were globally normalized for signal intensity using proportional scaling to remove confounding effects due to global CBF changes, with a threshold masking for grey matter of 0.8, allowing to include into the analysis only those voxels whose intensity exceeded the 80% of the maximal one.The voxel-based analyses were performed using SPM2 with a "one scan per subject, Ancova" design model, and significances were sought for the contrasts between healthy controls and the patient groups, and between the patient groups.For non-voxel based evaluation and analysis, the SPECT data were analyzed by a computerized brain atlas   allowingStepwise discriminant analysis was performed to compare clinical diagnosis as determined by the ADHD questionnaires and interview to the grouping according to some of the variables under investigation. This exploratory analysis was especially performed in order to identify the diagnostic factors accounting for the most of the group differences. The outcome of discriminant analysis resulted in discriminant functions (DF) that are the linear combinations of variables included in the analysis. The relevance of a DF is given by its canonical correlation (R), i.e., the total variance explained by each DF . On the basis of the scores computed for each subject, a classification matrix was computed to evaluate the efficiency of the analysis. Cases were classified as belonging to the group where the highest classification score was reached. Significance of the discriminant analysis was tested with aprox-F value.corrected < 0.05 at cluster level and puncorrected < 0.001 at voxel level were chosen. At voxel level, the false discovery rate (FDR) method for multiple comparison correction was also explored. In this latter case voxels were considered significant at a pcorrected < 0.05. Only those clusters containing more than 200 voxels were accepted as significant. This was based on the calculation of the partial volume effect resulting from the spatial resolution of the camera system. The significance threshold for the CBA analyses was set at p < 0.05.A threshold of p < 0.01 was set for the group differences on demographic data and rating scores. For group differences at SPM2, thresholds of p = 0.01 uncorrected for multiple comparisons for voxel height, pThe patients with low WURS-25 and WRAADDS scores were designated as the "Depression" subgroup (N = 16), and the patients with high WURS-25 and WRAADDS scores as the "Depression + ADHD" subgroup (N = 14). The patients endorsed the absence or presence of the ADHD symptoms as assessed by the questionnaires at the interview subsequent to filling in the ADHD-questionnaires. Two of the five patients with early hearing impairment were included in the "Depression" subgroup, and three in the "Depression + ADHD" subgroup. Three of the nine patients without audiological symptoms were included in "Depression", and six in "Depression + ADHD".The results of the thorough investigation of five patients included in the "Depression + ADHD" subgroup confirmed ADHD in three patients, and the predominantly inattentive subtype, Attention Deficit Disorder (ADD), in two patients.Demographic and other data are presented in Tables corrected = 0.024 at cluster-level and puncorrected < 0.001 at voxel-level), see Figure The SPM subtraction for the healthy controls minus "Depression + ADHD" revealed significantly decreased tracer uptake within the bilateral cerebellum in the patient group  = 1.749, p < 0.05) was found. There was decreased tracer uptake in the "Depression + ADHD" subgroup compared to controls in the bilateral cerebellum  = 13.429, p < 0.001) and in the caudate nuclei  = 10.013, p < 0.01).corrected < 0.001 at cluster-level; puncorrected < 0.001 and pFDR-corrected = 0.013 at voxel level) in "Depression + ADHD" within the bilateral BA 32 in the anterior cingulate cortex, in BAs 8, 9 and 10 in the prefrontal and middle frontal cortex, and in large portions of the frontal lobe white matter, see Figure The SPM subtraction for the "Depression + ADHD" minus "Depression" revealed a large cluster of highly significantly increased tracer uptake  = 1.605, p < 0.05) interaction. Tracer uptake was significantly decreased in "Depression + ADHD" as compared to "Depression" in the putamen  = 6.525, p < 0.05) and in the thalamus  = 5.209, p < 0.05).In discriminating between "Depression" and "Depression + ADHD", the WRAADDS subscale Impulsivity, the KSP subscale Socialization, and the thalamic tracer uptake were found to be the most useful variables. The 6-items Impulsivity subscale constitutes 17% of the WRAADDS items . Results for Socialization are presented in Table 99mTc-HMPAO uptake in the cerebellum at SPECT in chronically depressed females with adult-ADHD. No decrease of cerebellar 99mTc-HMPAO uptake was observed in chronically depressed females without ADHD. A relative increase of tracer uptake mainly in the frontal and anterior limbic cortex was found in the "Depression + ADHD" subgroup as compared to in "Depression". Self-rated scores for ADHD symptomatology followed by clinical interview were used to divide all the patients into subgroups with likely absence or presence of adult-ADHD. The DSM-IV-criteria for ADHD [In this study we report decreased for ADHD  were notSPECT provides image processing, tomographic reconstruction and image display. SPECT has a lower spatial resolution as compared to PET (8-10 mm versus 4-7 mm) and does not allow for quantitative assessment. Nevertheless, brain SPECT reflects CBF and neuronal activity distribution, resulting in reliable brain mapping with the use of radiopharmaceuticals that are more easily obtainable commercially than those applied at PET, making SPECT the most common functional imaging technique in routine examinations. Time resolution for perfusional SPECT is between two and three minutes, being lower than fMRI or methodologies based on magnetic activity of the brain (MEG). Image acquisition can be started up to some hours after administration still representing the brain distribution of the radiopharmaceutical at the moment of injection allowing for experiments to be performed in ideal psychological conditions in a quiet environment outside of the camera gantry.t-statistic based maps. CBA utilises the data from regions or VOIs able to feed multivariate analysis enabling the investigation of more general statistical effects. SPM analysis is conducted at cluster of voxel level while the CBA produces data at the larger VOI level. SPM does not usually analyse regions defined a priori and identifies changes only if clustering in a number of voxels exceed the determined threshold, often missing general effects. Conversely CBA cannot analyse clusters of voxel smaller than the pre-defined VOIs generally failing to detect fine regional changes. It is thus not surprising that the two methods might highlight different topographic changes in different regions. Hence, the double analysis underscores their complementarity in identifying global and local functional changes.SPECT was analyzed with SPM and CBA, three-dimensional digitized spatial standardization software which approach statistical analysis from different points of view. SPM implements univariate analysis creating 99mTc-HMPAO reflects various phenomena such as decreased blood flow, loss of cells or cellular constituents, decreased neuronal activity in functional circuits, and/or the metabolic status of the tissue. There is no overt linear correlation between the uptake of 99mTc-HMPAO and CBF as measured at PET using O-15 labeled water in healthy subjects [99mTc-HMPAO uptake and the cerebral glucose metabolic rate at PET has been reported in the left basal ganglia in depressive disorder [99mTc-HMPAO is intracellularly trapped and retained is also related to the metabolic state. 99mTc-HMPAO uptake can parallel the cellular content of reduced glutathione (GSH) [99mTc-HMPAO may be more dependent upon the redox activity than GSH content only [Decreased uptake (and retention) of the tracer subjects ,29. Uncone (GSH) , but theent only . GSH is ent only . The decent only .At the comparisons between the "Depression + ADHD" subgroup and controls, decreased tracer uptake within the cerebellum was found at both SPM and CBA in the patients. The cerebellum is involved in cognitive and behavioural control and emotional processing. Lesions in parts of the cerebellum are hypothesized to modulate actions via a "dysmetria of thought" . DecreasIn a longitudinal MRI study of children with ADHD, there were smaller volumes of the cerebellar vermis, and changes over time of the total cerebellar volume in the subgroup with worse outcome . A cerebIn a postmortem specimen study of major depression, decreased expression levels of subunits of mitochondrial complex I were found in the cerebellum. There were no alteration in any other of the analyzed brain region. A less consistent pattern of cerebellar reductions was observed in bipolar disorder along with increased subunit expression in the parieto-occipital cortex . In lighhypoactivity in adult-ADHD at PET [Increased tracer uptake at SPM in "Depression + ADHD" was found at the comparisons with "Depression" in BA 32 in the bilateral anterior cingulate cortex, BAs 8, 9 and 10 in the prefrontal and middle frontal cortex, and adjacent white matter. An increase of white matter volume has been reported in adult-ADHD [D at PET  and fMRID at PET  have beeD at PET . FailureD at PET . Time seD at PET .In a metaanalysis of neuro-imaging studies of major depression, "maximally abnormal" loci were identified within BA 32 and 24 in the anterior cingulate, and at the border of BAs 46 and 9 in the prefrontal cortex. Although more studies were categorized as reporting "overactivity", the fraction was not significant . However99mTc-HMPAO SPECT studies of depression. Increased frontal lobe tracer uptake has been reported in studies of atypical and chronic depression [99mTc-HMPAO uptake in the frontal lobe in the "Depression + ADHD" subgroup compared to in "Depression" may reflect cellular traces of some metabolic process of a more recent onset than the process affecting the cerebellum, or higher brain activity in "Depression + ADHD" to compensate for a "dysmetria of thought" due to a decrease of cerebellar function.Decreased tracer uptake in the frontal lobe has been reported in most pression . Increaspression . Compenspression . In the Decreased tracer uptake was found at CBA in "Depression + ADHD" in the caudate nuclei ("cognitive associative striatum") at the comparison with controls, and in the bilateral putamen ("sensorimotor striatum") and thalamus at the comparison with "Depression". A caudate involvement in ADHD has been reported . DecreasThe WRAADDS subscale Impulsivity and a Socialization scale were used in the discriminant analysis due to the specific and highly statistical group differences in these parameters. These factors, combined with the neurophysiological measure of the tracer uptake in the thalami, enabled a correct assignment of the cases to the "Depression" and the "Depression + ADHD" subgroups. A high discriminative value of the two scales was expected since the Impulsivity items comprises 10% of the 60 items used at the subgrouping, and since the Socialization items which were formulated 50 years ago deal with aspects of interpersonal difficulties often experienced in ADHD [see Additional file 99mTc-HMPAO SPECT due to observed gender differences using this method [Evaluating the genders separately may be advantageous in studies using s method . In studs method ,54,55.Controlling for age onset and depression severity might not be apt since, in females, more severe symptoms may be inherent characteristics of depression with comorbid adult-ADHD. Inconsistent results concerning age of onset of major depression have been reported in studies of depression with and without adult-ADHD ,56,57. NThe possibility that medication could have influenced the results cannot be fully ruled out since, although statistically unsignificant, 3/16 (19%) of the "Depression" subgroup patients, and 6/14 (43%) of the "Depression + ADHD" patients, had ongoing anti-depressant medications at the time of SPECT.99mTc-HMPAO, and thus the generalisability of our findings to adult-ADHD. No study has to our knowledge been performed reporting the prevalence of uni- or bilateral audiological symptoms of cochlear origin in adult-ADHD. There were no such symptoms in 3/16 (19%) of the patients in the "Depression" subgroup, or in 6/14 (43%) of the "Depression + ADHD" patients, an unsignificant difference. It seems unlikely that the decreased tracer uptake in "Depression + ADHD" compared to controls is related to audiological symptoms since the proportion is lower in "Depression + ADHD". ADHD is more common than expected in deaf children [It is difficult to evaluate the contribution of the depressive or the audiological symptoms or the heredity for audiological symptoms, in our patients on the brain uptake of children . Accordichildren , familiachildren . A role children ,62, is s in 6/14 % of the children ,64. For In the absence of well-validated and universally accepted diagnostic criteria for adult-ADHD ,65, our In this study applying the commonly available functional neuro-imaging method SPECT, we found decreased tracer uptake in the bilateral cerebellum in a group of depressed patients with adult-ADHD in comparison with healthy controls as verified by different three-dimensional digitized spatial standardization software. Increased tracer uptake in frontal lobe regions was observed in depressed patients with ADHD in comparison with depressed patients without ADHD tentatively reflecting a difference of the metabolic status in these brain regions which may be caused by some primary biochemical phenomenon, or reflect a compensatory mechanism, between these subgroups of depressed patients. Further studies are warranted exploring if depression with ADHD may represent endophenotype(s) of major depression, i.e., internal phenotypes that are not obvious to the unaided eye filling the gap between available descriptors, and between the gene and the elusive disease process, and therefore may help to resolve questions about etiological models .99mTc-HMPAO: 99mTc-d,l-hexamethylpropylene amine oxime; ADHD: Attention Deficit Hyperactivity Disorder; BA: Brodmann Area; CBA: Computerized Brain Atlas; CBF: Cerebral Blood Flow; DSM: Diagnostic and Statistical Manual of Mental Disorders; fMRI: functional Magnetic Resonance Imaging; KSP: Karolinska Scales of Personality; MADRS-S: Montgomery Aasberg Depression Rating Scale, 9-items version; MPD: Methylphenidate; MRI: Magnetic Resonance Imaging; PET: Positron Emission Tomography; SPECT: Single Photon Emission Computed Tomography; SPM: Statistical Parametric Mapping; VOI: Volumes Of Interest; WURS-25: Wender Utah Retrospective Scale, 25-items version; WRAADDS: Wender-Reimherr Adult Attention Deficit Disorder Scale.The authors declare that they have no competing interests.AG conceived of the study, the recruition and clinical investigation of the subjects, participated in the study design, and drafted the manuscript. DS participated in the methodological and statistical analysis. AV, ASC, HJ and SAL all participated in various parts of the methodological development and evaluation of brain imaging data. SB participated with the design of the neuropsychiatric test battery. MP participated in the design, coordination, statistical analysis and data interpretation of the study, and in the drafting and approval of the manuscript. All authors read and approved the final manuscript.The psychiatric and somatic comorbidity with adult-ADHD. A table presenting the reported psychiatric and somatic comorbidity with adult-ADHD. The issue of a putative shared pathophysiology is commented.Click here for fileThe Impulsivity and Socialization scales. Tables presenting the raw scores of the depressed subgroups on the Impulsivity and Socialization scales that were used in the discrimant analysis, and the individual items.Click here for file


Previously thought as a childhood disorder, attention-deficit hyperactivity disorder (ADHD) is reported to be spreading at an increasing rate and affecting 4% to 5% of the adult population. It is characterized by persistent problems of inattention, hyperactivity and impulsivity. We present the case of an adult ADHD patient intervened with neurocognitive psychotherapy. In spite of patients being almost normal or showing average functions in other domains, symptoms of poor and ill-sustained attention, disorganization and forgetfulness negatively affect the daily functioning of adults at the workplace and at home in numerous ways. Similarly, problems with organization often result in repeated loss or misplacement of items, inefficiency of effort and a disorderly workplace or home environment, also producing stress for oneself and one’s spouse or partner. It has generally been found that adult patients of ADHD resort to consultation only when it starts hampering their functioning level, with complaints focusing on poor functioning in professional or personal life rather than on ADHD symptoms. Thus detailed assessment becomes important in these cases to avoid misdiagnosis like depression, which may be overtly present as a comorbid condition. Despite the overall utility of stimulant and non-stimulant drugs in treating the majority of adults presenting with ADHD, there are limitations associated with drug treatment for this disorder. First, efficacy of drugs in these studies was documented as ‘effective’ for core symptoms, but there is little or almost no evidence that drug treatment has a positive effect on specific forms of functional impairment, such as poor motivation, disorganization, low self-esteem. Drug treatment alone may not be sufficient to remediate these deficits; some explicit skills and training in these areas may be necessary in adulthood. A significant subgroup of adults is apparently nonresponsive to drug treatment and thus also requires use of alternate interventions. Overall, the diagnosis and treatment of the disorder in adults can be a challenge because recent and integrative clinical guidelines are lacking. Keeping in mind that medication may not be fully effective for overall treatment of ADHD, especially of the associated functional impairment, researchers are looking towards other integrative therapeutic methods for treatment of adult ADHD. Neurocognitive psychotherapy is one of the models that have been developed, combining aspects of cognitive/behavioral therapy and cognitive rehabilitation that address both the neurocognitive and psychological aspects of ADHD. With this background, the following case study is reported to show the efficacy of neurocognitive psychotherapy in the treatment of adults with ADHD.Attention-deficit hyperactivity disorder (ADHD) typically develops during early childhood and often persists through adolescence and into adulthood. Indeed, for some patients, symptoms of ADHD do not become problematic until the individual is faced with the complex challenges of adulthood. ADHD is characterized by persistent problems of inattention, hyperactivity and impulsivity. These core symptoms lead to a wide range of impairments in adulthood, including lower educational attainment, lower vocational achievement, difficulties in interpersonal relationships and high risk for a wide range of additional psychiatric comorbidities. Once thought to be exclusively a disorder of childhood, it is now estimated that 4% of adults have ADHD  is an efficient and sensitive neuropsychological screening measure based on the Stroop procedure. The test has been standardized and validated for adults (18 years and older). Although the test is a screening tool for brain damage, it efficiently assesses environmental dependency and poor response inhibition by the subjects.The WCST was originally developed to assess abstract reasoning ability and the ability to shift cognitive strategy in response to changing environmental contingencies. WCST is considered a standard measure of “executive function,” requiring strategic planning, organized searching, utilizing environmental feedback to shift cognitive sets, directing behavior towards achieving a goal and modulating impulsive responding. It consists of 4 stimulus cards and 2 identical decks of 64 response cards with Figures of varying colors, forms and number. The subject’s task is to match the response cards to the stimulus cards based upon different criteria that keep on changing.The therapeutic program for this case is based on application of cognitive and behavioral principles and includes components intended to provide cognitive training in specific skills; reinforce and shape positive behavior; and impart new cognitions to maintain adaptive self-management behavior. The design of strategies was informed by neuropsychological theory and research concerning the core deficits in ADHD; thus, specific strategies were aimed to circumvent and compensate for deficits in sensitivity, delayed reinforce and in resistance to cognitive interference . The psychotherapy package was spanned over 10 weeks. Emphasis was put on practicing and maintaining of these strategies in daily life.The patient was imparted psychoeducation to enable him to understand his symptoms as an outgrowth of a treatable disorder and not as his personality faults. In most cases, psychoeducation brings about great relief to patients and encourages them to pursue treatment. Emphasis was laid upon better understanding of the condition and learning to manage symptoms rather than fighting with them.To enhance attention, the following strategies were used:Letter cancellation task: The patient was demonstrated and made to practice letter cancellation task with increasing complexity. Homework practice was also assigned, even using newspapers. Improvement was assessed by gradually decreasing the time limit.Matching shapes in initial session (shapes becoming more complex in nature as session progressed).Making meaningful words from jumbled-up words.Abstracting articles into themes or major points after reading them from a newspaper or a book.Considering patients’ occupational nature, organizational and planning skills were imparted emphasizing on the following aspects:Planning daily schedule for the present and the following day. At the end of the day, review of tasks completed was done.Breaking tasks into chunks and taking regular breaks: This helped in sustaining attention on a particular task, as well as eased the burden of doing it in a single spell.Maintaining a diary and ‘To-do’ list: Though the patient was using such technique earlier, it was regularized as daily activity.Prioritizing tasks and time management: Owing to variable workload, the patient was advised prioritizing the tasks and accordingly manage time.To improve the patient’s low self-esteem and poor motivation, he was helped in identifying his dysfunctional beliefs and their role in overall symptomatology. Emphasis was laid upon the following aspects:Identifying troubling conditionsBecoming aware of beliefs and thoughtsPinpointing negative or inaccurate thoughtsChallenging negative or inaccurate thoughtsChanging thoughts and beliefsUsing hopeful statementsFocusing on the positiveRe-labeling upsetting thoughtsEncouraging himselfThe patient had come with mixed set of problems. However, assessment revealed that inattention was the predominant problem that resulted in poor performance in job and decline in professional domain, further resulting in poor motivation and self-esteem. Findings in this case support the use of structured, combined approach of psychoeducation, Cognitive behaviour therapy (CBT) and cognitive training-based interventions; this approach was found to be effective in the patient and would be effective for adults with ADHD. Along with these elements, emphasis on regular practice and maintenance of these strategies in daily life is required to sustain the efficacy. Analyzing different components of intervention in this case, psychoeducation proved to be a vital part for the patient to get insight into the problem. Patient’s initial reliance on pharmacological intervention weakened by wider understanding of the problem and made space for inquiry about viable alternatives and made the patient to look upon the situation as treatable. The components of CBT mainly helped to improve the organizing skills of the patient in daily life; and to achieve overall improvement in self-esteem of the patient, motivation level and control over self-beliefs that helped maintain the symptoms. Cognitive training was the most vital part of the intervention package, which aimed upon improving attention, the principal area of intervention in ADHD. Findings show that the patient’s performance on neurocognitive measures declined to some extent at follow-up after initial improvement, suggesting continuous and prolonged practice to be a possible remedy for this. Finally the case supports neurocognitive psychotherapy, along with cognitive-behavioral and psychoeducative measures, as being effective in management of adult ADHD. It also indicated the need for long-term intervention program for sustained change in the patient’s behavior. These treatments, however, require further study for replication, extension and refinement.


The Attention Network test (ANT) gives measures of different aspects of the complex process of attention. We ask if children with Attention Deficit Hyperactivity Disorder (ADHD) will show a characteristic pattern of deficits on this test.The sample included 157 children (M = 10 years) who performed the child version of ANT as participants of the Bergen Child Study. Children with an ADHD diagnosis (N = 45) were compared to a group of children with other diagnoses (N = 55) and a group of children without any diagnosis (N = 57).The group of children with ADHD showed low accuracy scores and a variable response set, indicating an inattentive response style. No differences were found between the groups on RT and accuracy measures of the alerting, orienting, and conflict networks. A high correlation between full scale IQ (FSIQ) and ANT measures was only found in the ADHD group. When FSIQ score was included as a covariate, the group differences were not statistically significant on any ANT measure.The present study showed that accuracy and variability measures rather than measures of the three attention networks conveyed the characteristic pattern of deficits in children with ADHD. The results emphasized the importance of including these measures to extend the sensitivity of the ANT, and the importance of reporting results both with and without FSIQ as a covariate. Attention is a complex cognitive function, dependent on interacting neural systems of the brain. According to the Attention Network theory the systems can be subdivided into an alerting or vigilance network, a network of orientation or selection, and an executive or conflict network . A rangeThe three networks have been widely explored by using cue-target reaction time (RT) tasks  and taskMost studies using ANT have focused on the RT measures of the three attention networks, even though studies using measures from continuous performance tasks have shown that accuracy measures are more affected than RT measures in children with ADHD ,13. FurtThe aim of the present study was to find characteristic patterns of ANT results in children with ADHD by including measures of error types and variability in addition to the conventional measures of the three attention networks Table . From eastage 1); Development and Well-Being Assessment (DAWBA) [stage 2), and in-depth neuropsychiatric/neuropsychological assessment of a subsample of "DAWBA positive" (i.e. children who obtained a diagnosis according to DAWBA) and "DAWBA negative" children from stage 2. Children with a "chronic somatic disorder" reported by parents in stage 1 of the study [stage 2.The present study is part of the Bergen Child Study (BCS). The protocol and population of the stages in the first wave of BCS are described in detail in separate publications ,20, and  (DAWBA)  interviehe study  were incstage 3 was to investigate the neuropsychological function  of children with known mental health problems and normal controls. A total of 329 children met together with their parents for a 6 hours examination procedure at the Neuropsychology outpatient clinic at the University of Bergen. The examination included a diagnostic semi-structured interview of parent and child (Kiddie-Sads-Present and Lifetime Version) [The aim of Version) ; the WecVersion) , and theVersion) . Of the The study was approved by the Regional Committee of Ethics on Medical Research in Western Norway and by the Ombudsman for Privacy in Research, Norwegian Social Science Data Services Ltd.Kiddie-Sads-Present and Lifetime Version (Kiddie-Sads-PL) [Sads-PL)  was usedSads-PL) ,29. The Sads-PL) .The ANT used in the present study is the original "child version" [version"  downloadversion" . The tesversion" ,31. All version" , supplemversion" . This fiWISC-III [WISC-III  was usedWISC-III .The clinical examination was performed in an outpatient clinic at the University of Bergen. Trained psychologists administered the Kiddie-Sads-PL interview. The WISC-III and the ANT were administered by trained test-assistants, in a quiet room designed for testing. It was run on E-Prime software, on a stationary computer with a 17" computer screen. The children sat at a comfortable distance from the screen and used left and right thumb to press the left or the right mouse button, corresponding to a left and right pointing fish. The children were instructed to help feed the hungry fish as fast as they could by pushing the left or right button, according to which direction the fish was pointing. They were told that sometimes the fish would appear alone, and other times it would swim together with other fishes. In all cases, they were told to concentrate on the fish in the middle. They were also asked to keep their eyes on the fixation point during the presentations. The completion time was approximately 25 minutes.A Pearson correlation analysis with Bonferroni correction was computed, including the FSIQ score, age, and ANT measures. For FSIQ score, age, network measures, error measures, RT, standard error (SE) of RT, variability of SE, and vigilance measures, separate one-way between-groups ANOVAs were calculated. Main effects were further explored with post-hoc tests. The Tukey HSD was used to explore differences between groups where equivalence of variances were assumed, and the Games-Howell test was used if variances were heterogeneous. Bonferroni corrected independent-samples t-test was used to compare the results of children in the ADHD group who regularly took central stimulants and the results of the non-medicated children in the same diagnostic group.F = 3.311, p = .039, but Tukey HSD between group comparison revealed that the difference between the ADHD group and the other groups only bordered on significance . The mean FSIQ score for all participants was 90.9 .The overall accuracy on the ANT was 90.7%, and an analysis of the overall number of errors showed that 97.0% of all errors were wrong responses and omissions Table . Outlierp = .054). No main effect of group was found on the other measures.A one-way between groups ANOVA was performed separately for the overall Hit RT and the variability measures . A statistically significant main effect of group was found on the Hit RT SE measure Table  and 3. BA Bonferroni corrected Pearson's correlation analysis was performed between FSIQ scores, age and ANT measures Table . The anaF = 0,689, p = .504) and the Hit RT SE measure  = 0,316, p = .729).When FSIQ was included as a covariate in the ANOVA analyses, the main effect for group was no longer statistically significant for the overall error measure  was compared to the other ADHD children (N = 36) on selected ANT measures  and FSIQ scores. Bonferroni corrected independent-samples t-test showed no statistically significant difference between the two groups.The aim of the present study was to characterize patterns of ANT performance in children with an ADHD diagnosis. On the measures of the three attention networks, the results revealed no statistically significant differences between the group of children with ADHD, the group of children with other psychiatric diagnoses and the group of children without any diagnosis. However, the children diagnosed with ADHD showed a lower accuracy score as well as a more variable response pattern (i.e. a higher SE of RT) than the other groups.The results confirmed the expectation of lower accuracy scores in the ADHD group compared to what was shown in the other two groups. The ADHD group reported more wrong responses and showed a trend towards more omissions errors compared to the non-ADHD groups. The high number of omission errors in the ADHD group indicated a higher level of inattention than in children belonging to the two other groups, a finding that confirms earlier findings in studies using the Conners' CPT ,17. The Our findings with respect to vigilance are in conflict with results from studies using CPT, suggesting that loss of vigilance as the test progresses is characteristic of children with an ADHD diagnosis ,14,15. Id = .61) [The FSIQ score was strongly correlated with both error and variability measures, but only in the ADHD group. When included as a covariate, all differences between the ADHD group and the two other groups became non-significant. There is an ongoing debate whether or not one should control for IQ in studies of cognitive function in children with ADHD ,35-37. Sd = .61) . This had = .61) ,39 to ard = .61) , as doneWhile the IQ scores showed the strongest associations with errors, age was more strongly associated with the Hit RT and variability measures. Age was correlated with faster overall RT in the non-ADHD groups, confirming earlier findings that RT improves with age ,31. HoweBased on the behavioral measures of the attention networks, one should not exclude the possibility of a characteristic neural activity in children with ADHD, as suggested by Rodriguez  and KonrAs in all research including children with an ADHD diagnosis, the present results are colored by the high degree of heterogeneity within the diagnostic group. In the present study, information about subgroups of ADHD and symptom load was not included. Both Booth  and RodrThe main strength of the study was the case-control selected sample of children with ADHD, and that the results probably are less biased by co-morbid problems than clinical studies. However, no child was excluded due to a low FSIQ score, although some of the BCS participants with very low FSIQ score were excluded because they were unable to perform the ANT. The high correlations between the FSIQ score and error and variability measures in the ADHD group indicate that by excluding children with low total IQ scores, one may have excluded a specific group of ADHD children .Although there have been several studies of the neuropsychological characteristics and the neural basis of ADHD, the deficits of attention in children with this behavioral diagnosis are still poorly understood. To conduct studies of this complex issue, appropriate neurocognitive models that operationalize different aspects of the attention system are necessary. The attention network theory provides one such model and can be used both in group studies and in the clinical evaluation of individual children. In a neuropsychological examination, the range of variables from the ANT may help to characterize the strengths and difficulties of a child. Studies of the attention networks in children with ADHD may contribute to a better understanding of the disorder and to the development of appropriatetraining and treatment methods .The results in the present study support the notion that accuracy measures rather than RT measures are sensitive to characteristic deficits in children with ADHD ,13. The The author(s) declare that they have no competing interests.SA has been responsible for the data analysis and the writing of the manuscript. AJL designed and coordinated the study, supervised the data analysis and the writing process. LS participated in the acquisition of data, discussions about the data analyses and commented on the written drafts of the manuscript. All authors have read and approved the final manuscript.ADHD: Attention Deficit Hyperactivity Disorder; ANT: Attention Network Test; BCS: Bergen Child Study; CPT: Continuous Performance Test; FSIQ: Full Scale IQ; ODD: Oppositional Defiant Disorder; RT: Reaction time; Kiddie-Sads-PL: Kiddie-Sads-Present and Lifetime Version; WISC-III: Wechsler Intelligence Scale for Children-III.


An abundance of literature is dedicated to research for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Most, is in the area of pharmacological therapies with less emphasis in psychotherapy and psychosocial interventions and even less in the area of complementary and alternative medicine (CAM).The use of CAM has increased over the years, especially for developmental and behavioral disorders, such as ADHD. 60–65% of parents with children with ADHD have used CAM. Medical evidence supports a multidisciplinary approach  for the best clinical outcomes. The Neuro Emotional Technique (NET), a branch of Chiropractic, was designed to address the biopsychosocial aspects of acute and chronic conditions including non-musculoskeletal conditions. Anecdotally, it has been suggested that ADHD may be managed effectively by NET.A placebo controlled, double blind randomised clinical trial was designed to assess the effectiveness of NET on a cohort of children with medically diagnosed ADHD.Children aged 5–12 years who met the inclusion criteria were randomised to one of three groups. The control group continued on their existing medical regimen and the intervention and placebo groups had the addition of the NET and sham NET protocols added to their regimen respectively. These two groups attended a clinical facility twice a week for the first month and then once a month for six months.The Conners' Parent and Teacher Rating Scales (CRS) were used at the start of the study to establish baseline data and then in one month and in seven months time, at the conclusion of the study. The primary outcome measures chosen were the Conners' ADHD Index and Conners' Global Index. The secondary outcome measures chosen were the DSM-IV: Inattentive, the DSM-IV:Hyperactive-Impulsive, and the DSM-IV:Total subscales from the Conners' Rating Scales, monitoring changes in inattention, hyperactivity and impulsivity.Calculations for the sample size were set with a significance level of 0.05 and the power of 80%, yielding a sample size of 93.The present study should provide information as to whether the addition of NET to an existing medical regimen can improve outcomes for children with ADHD.Australian New Zealand Clinical Trial Registration Number: ANZCTRN 012606000332527 There is an abundance of literature dedicated to research for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) -5. Most The use of CAM therapies, has increased over the years, especially for the developmental and behavioral disorders, such as ADHD,11-14. AMedical evidence supports a multidisciplinary approach  for children and adolescents diagnosed with ADHD for the best clinical outcomes ,8,26-32.The best clinical outcomes are produced when an integrated biopsychosocial approach is employed for children with ADHD ,37-39. TEvidence suggests that 10–30% of children with ADHD who have been prescribed stimulant medications, do not show clinically significant outcomes, and others experience side-effects and need to discontinue their medications ,32,41-43The most common side effects of stimulant medications are appetite suppression, weight loss, sleep disturbances, irritability, stomach aches, headaches, rashes, and occasionally the development or aggravation of tics ,41,43,44For these children, additional strategies need to be implemented in order to achieve a successful outcome ,42. PareThe objectives of this research are to:1. To determine whether the addition of the Neuro Emotional Technique , to an existing medical regimen can improve clinical outcomes  for children with medically diagnosed ADHD.2. Furthermore, to determine the responses in the short term (i.e. one month) and medium term (seven months).Ethics approved, registered, interdisciplinary, placebo controlled, double blind, randomized clinical trial.Four private clinics in Sydney, Australia.Four chiropractors, three male and one female volunteered their time and services to administer interventions to the participants of the study at no cost. The chiropractors had varied tertiary qualifications: one had Bachelor of Medical Sciences and a Master of Chiropractic; two had a Bachelor of Science and a Master of Chiropractic and one had Bachelor of Science and a Graduate Diploma of Chiropractic. All of the chiropractors had undergone the four NET training workshops over a two year period, and had passed the certification exams in both theory and practice, and a thus were qualified as NET certified practitioners. These practitioners were chosen on the basis that they were experts in the field, were certified and agreed to abide by the study protocols.Parents were initially screened on the phone, and their children were included in the study if inclusion criteria were met. Inclusion criteria comprised: children aged between 5–12 years; children with a medical diagnosis of ADHD for minimum of 2 months, diagnosed by Pediatrician, Psychiatrist or Clinical Psychologist; informed verbal and written consent from parents and participants; children currently undergoing any interventions  or children with the diagnosis of ADHD who have not undergone any treatment; and children who presented with the following comorbid disorders – Conduct Disorder, Oppositional Defiant Disorder, Learning Disabilities, and Anxiety Disorders. Any children who did not meet the inclusion criteria, or who met the exclusion criteria were excluded from the study. Exclusion criteria comprised: A diagnosis of Language difficulties, Mood Disorders (eg. Depressive Disorder or Bipolar Disorder), Communication Disorder, mutism, Pervasive Developmental Disorder (eg. Autism or Asperger's Disorder), Psychosis, profound deafness and other physical or mental disabilities that would prevent participants interacting physically and verbally with the care provider during the consultation; any changes in medications during the course of the study, and any child or parent who had previously undergone any NET treatment.The Diagnostic and Statistical Manual of Mental Disorders ADHD diagnostic criteria ,54 were The ratings scales were administered pre-intervention to establish baseline data, and were used as outcome assessments to measure the intervention effects at the end of the first month and at the conclusion of the study i.e. in seven months. Of the 14 subscales described in the CPRS-R:L and the 13 subscales described in the CTRS-R:L, two were chosen as primary outcome measures (POMs) and three were chosen as secondary outcome measures (SOMs). Primary outcome measures included Conners' ADHD Index and Conners' Global Index Total subscales H and K respectively. The secondary outcome measures included DSM-IV:Inattentive, DSM-IV:Hyperactive-Impulsive and DSM-IV:Total, subscales L, M, and N respectively.The Conners' ADHD Index is used to distinguish ADHD children from non-clinical children, and is considered a good screening tool ,59. The The DSM-IV:Inattentive subscale was chosen as it has a correlation with the DSM-IV diagnostic criteria for the Inattentive Subtype of ADHD, and focuses on the symptom of inattention. The DSM-IV:Hyperactive-Impulsive subscale was chosen as it has a correlation with the DSM-IV diagnostic criteria for the Hyperactive-Impulsive Subtype of ADHD, and focuses on the symptoms of hyperactivity and impulsivity. The DSM-IV:Total subscale was chosen as it has a correlation with the DSM-IV diagnostic criteria for the Combined Subtype of ADHD, and focuses on all core features of ADHD  .Eligible participants were randomly allocated to one of three groups A, B, & C . The "QuickCalcs" program from the GraphPad Software  was usedEach number and its randomised letter  were placed in an opaque envelope. Each envelope was numbered consecutively from 1–150.As each parent called to have their child screened they were allocated the next consecutive number once they were eligible, so that eligible participant no. 1 was allocated to envelope no. 1, etc. The screener was unaware of the sequence of group allocation at the time of screening, hence allocation was concealed at time of recruiting.Participants were blinded as to which intervention group they were allocated to, in an attempt to control for the Hawthorne Effect. Parents and teachers were blinded to which intervention group the children were allocated to, in an attempt to minimize rater bias when completing rating scales i.e. CPRS-R:L and CTRS-R:L. The registered Psychologist and the Clinical Psychologist were blinded as to which group participants were allocated to, in order to minimize bias when scoring and interpreting the data from the CPRS-R:L and CTRS-R:L.The NET practitioners were not blinded in this study as they needed to know which participants were receiving which intervention, i.e. treatment versus sham protocol. The parents of the control group were also aware that their children were in the control group awaiting treatment at the completion of the study.Calculations for the sample size were set with a significance level of 0.05 and the power of 80%.As there are no prior studies conducted in the area of chiropractic or NET for an ADHD cohort, for power analysis purposes a SD of 6.7 was adopted based on data from Shortt , yieldinRecruitment for the study commenced in July 2006 and the first participant was enrolled in August 2006 and the last participant completed the study in March 2008. Each participant that qualified and was enrolled into the study and had their own start date, hence the staggered starts and as a result the study took 17 months to complete.As part of the phone screening and the informed consent forms the parents of the participants were advised that they were free to withdraw their child/children from the study at any stage without any consequences.Group A, the sham group, continued with their existing program and the sham protocol was added to their regimen. Group B, the treatment group, continued with their existing program and the NET protocol was added to their regimen. The participants in groups A and B attended a clinical facility for the first month and received eight treatments (two treatments per week) for approximately 15–20 minute sessions. Then, they were scheduled for another six treatments over the next six months (i.e. one treatment per month). Group C, the control group, consisted of children who continued with their existing ADHD treatment regimen as prescribed by their pediatrician, clinical psychologist and/or medical doctor.NET is a methodology of finding and removing Neuro Emotional Complexes (NECs). A NEC is defined as a subjective maladaptation syndrome adopted by the organism in response to a real or perceived threat to any aspect of its survival . NET hasWalker  describeMuscle testing is non-invasive system of evaluating the function of the body . NET proNET is a system that evaluates structural, emotional, and chemical  aspects of a patient's health and wellbeing using the manual muscle testing procedure as a diagnostic guide. Emphasis must be made that for the purpose of this study, the emotional aspects were the only issues addressed, investigating whether ones "emotional reality" affected one's mental wellbeing and behaviour patterns.Firstly, the participants were evaluated for a healthy deltoid muscle, capable of resisting the testing pressure of the practitioner. The participants were seated, and asked to raise their arm 90 degrees to their body, keeping their elbow straight. Pressure was applied to the participant's wrist, whilst they were asked to "hold strong", (i.e. resist pressure). A practice trial was conducted to familiarize the participants with muscle testing procedure (MTP). This MTP has shown good inter-examiner reliability .The participants were asked to make the following statement, "I'm OK, keeping still."If MTP to this statement tested weak, it is said that the participant is non-congruent with that concept.Next, the participants were asked to continually repeat that statement whilst the practitioner continued the MTP with one hand and with the other hand palpated the different meridian access points (MAPs) on the participant's body. Each MAP is considered to be a specific skin point which, based on acupuncture theory is associated with certain emotions . Figure and 3When the participants tested strong to the statement and a MAP, it was considered that there was an emotional component related to their problem.The practitioner continued to explore the psychosomatic connection by making a series of statements. Using the MTP the concept of an "original event" was being investigated. The current "emotion" was related to a past event by the asking of "when, where, and who" questions. This was done to uncover why there appeared to be retained conditioned response to a previous stressful event.The untested theory of NET suggests that the stimuli associated with the original event become associated via a process of Pavlovian conditioning, and are then reproduced through a process of repetition compulsion.The participants were provided a statement that connected past and present events relating to their "emotion". If the MTP using this statement, tested weak, it indicated that the problem had been recalled.Next, the participants were asked to contemplate the original event and associated feelings in the conscious mind, and were given kinaesthetic stimulation of spinal segments. The conscious recall of past events with the association of normalised stimuli is theorised to condition the original event with positive stimuli. This is believed to break the cycle of the conditioned (learnt) response by reactivating the original negative event and it's ongoing repetition and pairing it with a competing somatic stimulus.Lastly, the practitioner retested the participant by using MTP to check the original statement "I'm OK keeping still". When the MTP tests strong, this indicates the participant is now congruent with that statement.This procedure was repeated using 16 different referential statements. During the first month of treatment two referential statements per visit were used and tested. If the MTP tested weak, implying the participant was not congruent with the concept in that particular statement, then the NET protocol ensued. Please see Table The sham protocol was designed to mimic the real NET treatment protocol, however without the therapeutic benefits. The sham protocol incorporated the MTP throughout the procedure, with different sets of statements and tapping on the back. The set of statements used were not related to the treatment protocol, but instead used for testing of congruent and non-congruent reactions to statements like, " my name is John" and then "my name is Robert" i.e. the child's name first then another name. See Table As there are no known side effects and there have not been any reports of adverse reactions to the NET protocol, we do not anticipate that any participants will be exposed to any unnecessary risks. However, in the event that a child becomes emotionally distressed during the protocol, the procedure will be terminated. Support counselling will be offered by qualified psychotherapists and counsellors for the child at no expense to the parents. These professionals have all been approved for the study by the university Ethics Committee and have also undergone background screening and have been approved to work with children.The trial protocol was reviewed by the Macquarie University Human Ethics Committee  and was granted Human Ethics Approval (HE26AUG2005-M04261). As a prerequisite to conducting research with children, the Ethics committee required all those involved with the study undergo background screening as part of the "Working With Children Check". All those involved in the study were approved and ethics was granted.Furthermore, as part of this study, an application was made to the Department of Education and Training and a State Education Research Approval was granted (SERAP #06.350). This enabled the researchers to send questionnaires to the teachers of the participants of the study.All of the parents of the participants were issued with two copies of the informed consent forms (one to keep and one to return to the university). The informed consent form conveyed the following information: the names of the chief investigator, the supervisors and the four practitioners administering the interventions; the name of the university and the department conducting the research; a brief description of the control, treatment and sham groups; the duration of the study; the questionnaires used; the Ethics approval and contact details of the Ethics officer; the right to withdraw their child at any time; in the event a child becomes distressed the back-up counselling services available; the involvement of teachers; and the fact that the results of the study will be disseminated via conferences and publications whilst maintaining the children's privacy.th Edition [Demographic and baseline characteristics of participant variables will be compared between the three randomised groups using the Restricted Maximum Likelihood (REML) in GenStat 10 Edition .th Edition [The primary analysis will compare outcomes for each primary and secondary outcome measure between the three groups  using the Restricted Maximum Likelihood (REML) in GenStat 10 Edition , to esti Edition .An intention-to-treat (ITT) analysis will be undertaken of the one month and seven month data from the CPRS-R:L and CTRS-R:L for the participants who commenced the study but did not complete.We have a presented the design and the protocol for the RCT of NET for childhood ADHD. The participants of this study will have NET added to their existing medical regimen  and will be monitored for changes in their outcomes  in the short term (one month) and medium term (7 months). Completion of this trial will help provide the answer to the question "does chiropractic (NET) have a role to play in the management of children with ADHD?" Results of this RCT will be disseminated at the completion of the study.th Edition; CRS: Conners' rating Scales; CPRS-R:L: Conners' Parent Rating Scale Revised Long Version; CTRS-R:L: Conners' Teacher Rating Scale Revised Long Version; POMs: Primary Outcome Measures; SOMs: Secondary Outcome Measures; CGI: Conners' Global Index; CBT: Cognitive Behavioral Therapy; NECs: Neuro Emotional Complex; MTP: Muscle Testing Procedure; SERAP: State Education Research Approval; ANOVA: Analysis of Variance; ITT: Intention-to-Treat Analysis; CI: Confidence Intervals; RCT: Randomized Controlled Trial.NET: Neuro Emotional Technique; ADHD: Attention Deficit Hyperactivity Disorder; CAM: Complementary and Alternative Medicine; CONSORT: Consolidated Standard of Reporting Trials; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders 4No funding was received for this study or for the preparation of this manuscript.The chief investigator FK and secondary supervisor RB declare that they have no competing interests.The primary supervisor HP is a part-time employee of the ONE (Our Net Effect) Foundation, which is the research arm of NET and a non-profit organisation. The organisations interests relate to establishing natural healing as standardised care through NET research, education and public service.FK conceived the research project.FK, HP, and RB designed the study.FK designed and tailored the protocol for the ADHD cohort.All authors contributed to the writing of the manuscript.All authors read and approved the final manuscript.


The degree of ADHD-related difficulties – reflecting overall impairment, social functioning, and quality of life – may be perceived differently by adolescent patients, parents and physicians. The primary aim of this study was to investigate ADHD-related difficulties during atomoxetine treatment, as perceived by the three different raters. Secondary objectives focused on effectiveness and tolerability of atomoxetine treatment in a population of adolescent patients with ADHD.Adolescents with ADHD, aged 12–17 years, received open-label atomoxetine (0.5–1.2 mg/kg/day) up to 24 weeks. ADHD-related difficulties at various times of the day were rated using the Global Impression of Perceived Difficulties (GIPD) instrument. Inter-rater agreement was analyzed using Cohen's Kappa with 95% confidence intervals (95% CI). ADHD-Rating Scale (ADHD-RS) and Clinical Global Impression Severity (GGI-S) scores were assessed by the investigator; and spontaneous adverse events, vital signs and laboratory parameters were collected for tolerability assessments.159 patients received atomoxetine. Patients' baseline mean GIPD total ratings were significantly lower than parents' and physicians' scores . For all raters, GIPD scores significantly improved over time. Changes were greatest within the first two weeks. Kappa coefficients varied between 0.186  and 0.662 , with strongest agreements between parent and physician assessments, and significant improvements of patient/physician agreements over time (based on 95% CIs). ADHD-RS and CGI-S scores significantly improved over the course of the study (based on 95% CIs). Tolerability results were consistent with earlier reports.ADHD-related difficulties were perceived differently by the raters in this open-label trial, but consistently improved during atomoxetine treatment. The GIPD instrument appeared sensitive to treatment-related change. These primarily quantitative findings may guide future studies to more systematically investigate the clinical and practical relevance of the differences observed. Additionally, in order to further validate these results, placebo- and comparator-controlled trials are recommended as well as inclusion of healthy controls and other patient populations.Clinical Trial Registry: ClinicalTrials.gov: NCT00191737 Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and hyperactivity and affects 3–7% of school-aged children in the United States . ADHD isBeyond the improvement of core symptoms during ADHD treatment, there is growing appreciation of possible additional patient and family benefits, including QoL and functional outcome parameters -10.Atomoxetine is a non-stimulant treatment option for ADHD ,12, effiHowever, when assessing QoL in adolescents with ADHD, both, symptom severity and ADHD-related difficulties, may be perceived and rated differently by patients, parents, and physicians . For exaprimary objective of this study was to investigate the severity of ADHD-related difficulties perceived by patients, parents, and physicians during atomoxetine treatment, and to compare these three perspectives over the course of the study, using the Global Impression of Perceived Difficulties (GIPD) instrument. The psychometric properties of this brief scale have recently been reported  at baseline to 16.7 [15.0 to 18.3] at week 2 . Total scores were at 12.9 [11.4 to 14.4] by week 8, and at 13.3 [11.7 to 15.0] by the end of week 24. The course was largely parallel for both ADHD subtypes Figure . Over thLooking at the ADHD-RS sub-scores, courses of the Hyperactivity-Impulsivity and Inattention sub-scores followed the general pattern shown for the total score. Combined subtype of ADHD was again associated with statistically significantly higher mean scores than the predominantly inattentive subtype, this held for the Hyperactivity-Impulsivity subscore but not the Inattention subscore Figures  and 3c.The mean CGI-S-ADHD score (LOCF) for the overall sample significantly decreased from 4.8 [95%CI 4.7 to 5.0] at baseline to 3.4 [3.2 to 3.6] at week 8 and stayed stable thereafter until week 24 (3.3 [3.1 to 3.5]). Regarding the ADHD-subtypes, a comparable decrease was observed. The mean CGI-S-ADHD scores of the predominantly inattentive subtype tended to be slightly lower than the scores of the combined type over the entire course of the study, but the differences did not reach statistical significance  patients over the entire study period. Adverse events reported in more than 5% of all patients (N = 159) were: fatigue 45 (28.3%), headache 38 (23.9%), nausea 30 (18.9%), nasopharyngitis 21 (13.2%), vomiting 21 (13.2%), upper abdominal pain 12 (7.5%), decreased appetite 12 (7.5%), dizziness 12 (7.5%), diarrhea 9 (5.7%). In 82 (51.6%) patients the investigators considered the adverse event as possibly related to atomoxetine. Adverse events reported in more than 5% of the patients and rated as possibly related to atomoxetine were: fatigue , nausea , headache , upper abdominal pain , decreased appetite , dizziness 9 (5.7%) and vomiting 9 (5.7%). There were 8 patients with serious adverse events, which were considered related to atomoxetine in two patients .Treatment-emergent adverse events led to discontinuation in 7 (4.4%) patients: alopecia, decreased appetite, drug abuse  fatigue, vasoconstriction , vertigo and vomiting in 1 (0.6%) patient each. Except for fatigue and drug abuse, all these adverse events were rated as possibly related to treatment.Mean laboratory parameters, including liver function tests, were found within normal ranges with only minor fluctuations over the course of the study . For vital signs, increases in systolic and diastolic blood pressure  and heart rate were observed as: SBP: BL, 112.6 ± 13.9 mmHg; wk 8, 115.4 ± 12.9, wk 24, 117.5 ± 12.1. DBP: BL, 70.3 ± 10.0 mmHg; wk 8, 72.8 ± 8.8; wk 24, 73.8 ± 9.2. Heart rate: BL, 77.9 ± 10.7 bpm; wk 8, 87.1 ± 13.6; week 24, 84.8 ± 12.0.To our knowledge, this is the largest single study focusing on adolescent ADHD patients treated with atomoxetine ,19: 159 As the primary objective, we investigated possible differences in perceptions of ADHD-related difficulties by patients, parents, and physicians using the recently devised GIPD instrument . In evalIn this study with adolescent ADHD patients, the degree of the ADHD-related difficulties was rated statistically significantly lower by the patients than by their parents or their physicians. In contrast, the difference between the parent and physician GIPD ratings was small. With reference to the methodological approach chosen in this trial, it appeared that these patients subjectively perceived the degree of their ADHD-related difficulties as lower than their parents or physicians did. These findings were consistent with the parallel open-label study in children with ADHD , as wellInterestingly, the baseline self-reports of adolescent ADHD patients with the combined subtype vs. the predominantly inattentive subtype did not differ as to the severity of perceived ADHD-related difficulties. In contrast, parents and physicians rated the difficulties of the patients with the combined type as slightly more severe (n. s.) than those of the patients with the predominantly inattentive type, potentially corresponding to the clinical observation of third-party raters' assessing the impact of inattention as less burdensome.The differences between the three perspectives persisted over the entire observation period. At the end of the acute treatment period (week 8), GIPD Total scores were statistically significantly reduced for all three rater groups , This level of improvement persisted until week 24. In general, these findings also held for the single-item GIPD evening and morning assessments. This statistically significant and consistent decline in ADHD-related difficulties during atomoxetine treatment may cautiously be interpreted to reflect an improvement in patient overall impairment, social functioning, and QoL in this adolescent patient population. Again, findings were highly consistent with the parallel study in children . In addiPrevious studies that used more specific instruments to assess QoL in children and adolescents with ADHD ,28-30,43As summarized by Steele et al. , studiesCohen's Kappa coefficients varied considerably across the three rater groups and the course of the study, with strongest (moderate) agreements between physician and parent assessments, and significant improvements of patient/physician agreements over time. Study design features, with choosing a nearly naturalistic sequence of applying instruments and using information as in an office-setting, may have impacted on this outcome.With respect to the secondary objectives of this study, mean ADHD-RS Total scores decreased statistically significantly over time, with -15.6 (-54.9%) mean change, from a relatively low baseline (28.4) to week 8 (12.9) in this adolescent population. Wilens et al.  reportedThe percentage of ADHD-RS mean change for adolescents reported here was generally in line with several placebo-controlled trials – involving both children and adolescents – which showed efficacy with atomoxetine treatment ,13-15. IBased on ADHD-RS assessments, effectiveness was shown both for the combined type and the predominantly inattentive type of ADHD. This finding could be anticipated since atomoxetine has been known to improve both hyperactive/impulsive and inattentive symptoms of ADHD ,13,15,44Mean CGI-S scores also significantly improved over time cf. ,13,15], ,15, 13,1In general, the pattern of treatment-emergent adverse events in this study appeared to be in line with that reported in randomized, placebo-controlled trials in children ,15,16 orThe reported data from this study should be interpreted cautiously in the context of its methodological limitations: The open-label study design in general is prone to rater bias, although symptom improvements over time were corresponding to results from double-blind placebo-controlled trials. And, as often observed when using several instruments, there will be overlap in constructs measured by the various scales . The seqIn summary, adolescent patients rated their ADHD-related difficulties, which can be considered to reflect overall impairment, social functioning, and QoL, as lower than either parents or physicians did. All three rater groups reported clear reductions in severity of these perceived difficulties over time, for total, evening, and morning assessments. The different views, the patient perspective on daily difficulties in particular, may provide important additional information when evaluating effectiveness of a treatment [cf ] and adjThe reported differences in overall GIPD ratings and their statistical relevance may guide clinicians and researchers to collect more detailed differential data on actual impairment and quality of life from both adolescent ADHD patients and their parents, if applying more elaborate techniques and measures, both in clinical work and in future studies focussing on HRQoL. Additionally, comparative research is needed on the impact of various ADHD medications, focusing not only on the core symptoms of ADHD but as well on the health-related quality of life and functional outcomes of both patients and families, considering age and gender effects across the life-span.RWD is a former employee of Lilly Deutschland and now holds an Eli Lilly Endowed Chair of Pediatric Psychopharmacology. PMW, AS, AM, and ML are full-time employees of Lilly Deutschland, RWD and PMW own Eli Lilly & Co. stock. GL has received research grants and speaker honoraria from Eli Lilly & Co. and is member of a Lilly Advisory Board.RWD, PMW, ML and AS developed the clinical trial. AS developed the analyses reported in this manuscript. All authors participated in development of the GIPD scale and the interpretation of data. RWD, AS and AM drafted the manuscript, PMW, ML, KS and GL revised it critically for important intellectual content. All authors read and approved the final manuscript.


Expressed Emotions (EE) are associated with oppositional behavior (OPB) in children with Attention Deficit/Hyperactivity Disorder (ADHD). EE has been linked to altered stress responses in some disorders, but ADHD has not been studied. We test the hypothesis that OPB in ADHD is mediated by altered stress-related cortisol reactivity to EE.Two groups of children (with/without ADHD) and their respective parents were randomly assigned to two different conditions with/without negative emotion and participated in an emotion provocation task. Parents' EE, their ratings of their children's OPB and their children's salivary cortisol levels were measured.Low parental warmth was associated with OPB in ADHD. High levels of parental EE elicited a larger cortisol response. Stress-related cortisol reactivity mediated the EE-OPB link for all children. This highlights the general importance of parent-child interactions on externalizing behavior problems.High EE is a salient stressor for ADHD children that leads to increased levels of cortisol and OPB. The development of OPB might be mediated by the stress-response to high EE. Expressed Emotion  directed by a caregiver towards a psychiatric patient, predicts relapse ,2 and isThe mechanism that might link EE and OPB in children with ADHD remains unclear. Taylor  has suggFirst, there is evidence, that hypothalamic-pituitary-adrenal (HPA) axis regulation is altered in children with ADHD. Low basal cortisol levels, weak acute HPA reactivity and abnormal diurnal cortisol rhythms have been reported -18 and sSecond, patients with OPB and ADHD may be particularly likely to show altered physiological reactivity. In a study by Freitag et al.  childrenThird, EE may alter stress-related arousal patterns. Tarrier et al.  demonstrDespite these encouraging effects there has been no investigation of EE effects on HPA-axis activity and/or whether such effects might predict the development of OPB in ADHD children. Here we investigate this hypothesis making the following predictions: (1) EE in ADHD families is associated with oppositional behavior in the children with ADHD; (2) the cortisol response to a psychosocially stressful experimental condition is decreased for ADHD children with/without OPB, and this contrasts with the absence of differences between cases and controls in a positive control condition; (3) altered stress reactivity mediates the link between EE and the presence of oppositional behavior.© established that a total of 128 participants would be required to test for medium group effects when applying multivariate tests  = 3.91, Lambda = 13.33, α = 0.05, β = 0.95, f = 0.25); thus our sample missed the optimal sample size by five individuals. ADHD Children were recruited from a large outpatient clinic at the University Clinic for Child and Adolescent Psychiatry and Psychotherapy, Essen, Germany. The ADHD diagnosis was based on the Parental Account of Childhood Symptoms (PACS); a DSM-IV based, semi-structured, standardized, trained investigator-based (first author) interview that has good inter-rater reliability . The PA - 0.96; ). There ADHD symptoms and oppositional scores were rated with the long version of the Conners' parent and teacher rating scales . The quTRS-R:L; . T-scoreTRS-R:L;  and missExpressed emotion was measured using the Five Minute Speech Sample . A traie (FMSS: ), a mease  all the hits the child made on a short stop-signal computer task [We used the novel experimental attitude priming task (APT) described by Hooley et al. , to creater task ,45 or crSaliva samples of cortisol were used as a marker for the acute response to stress in both parents and children. Over the period of one hour, five samples were taken. The first one (T1) served as baseline measure. The second one (T2) was taken while the child worked on the computer (during stress task); the third one (T3) was taken immediately after the stress task; T4 and T5 were taken 30 and 60 minutes after the baseline measures, that is 15 respectively 30 minutes after the stress task. For the detection of un-elicited cortisol response, saliva samples were subjected to standard techniques. Briefly, participants were asked to place a cotton wool swab into their mouth for two minutes. The swab was subsequently placed into a prepared tube, which was stored at room temperature until collection of all five samples. Tubes were then centrifuged for 10 min and stored at -20°C prior to analysis. Samples were inspected for blood contamination before further analysis. All samples yielded clear saliva of low viscosity. Saliva flow was determined by weighing the tubes before and after saliva sampling. Cortisol concentration in saliva was measured using a commercially available, coated-tube radioimmunoassay validated for that matrix . MeasureAll children and their parents arrived at 8 a.m. to ensure that no activities except breakfast and the trip to the clinic occurred that could influence early morning free cortisol levels ,49. AfteData reduction and analyses were carried out using the statistical package SPSS 15.0. Differences in Conners' rating scales and EE measures between ADHD children and controls were compared with an ANOVA. Additionally oppositionality ratings were entered as covariate to control possible influences on EE measures, since comorbid OPB strongly influences the association between ADHD and EE ,14. InflTo establish a mediation effect, first the predictor-criterion correlation must be significant and meaningful. Second, the predictor must show a significant association with the putative mediator. Third, the mediator must be associated with the criterion measure, and finally, the predictor-criterion correlation must be attenuated when the mediator variable is entered into the mix ,51. ThusChildren with ADHD scored higher than control children on all Conners' subscales, with T-scores ranging between 1.5 to 2 standard deviations above the mean, except for parental anxiety ratings  nor on the following four measures  nor Conners' parent  or teacher  ratings of the DSM-IV ADHD-combined type correlated significantly with medication status. There were no differences in FMSS ratings for children with or without medication  = .049, p = .826). For ADHD children Perceived Criticism (PC) did not correlate significantly with the assigned condition nor with parental FMSS ratings, suggesting that they did not perceive the criticism expressed by their parents. For the control children, on the other hand, there were significant correlations between assigned condition and PC at both times (see table There were no influences of medication status on any of the measures taken. Neither cortisol levels (μg/dL) at baseline  = 13.422, p < .001, η2 = .105; for details in FMSS-ratings see table F = 0.008, p = .929), but age did not  = 8.38, p < .001, η2 = .316). Of the parents with ADHD children, 28.6% were rated with High EE, 6.3% showed EOI, and 4.8% showed both High EE and EOI, whereas 54% showed Low EE. In comparison, parents of control children showed mostly Low EE (83.3%); 5% were highly critical and 8.3% showed EOI. Effects were due to higher criticism/hostility (d 1.07) and reduced warmth (d -.84) in parents of ADHD children, but not to EOI. A stepwise linear regression with all FMSS measures was used to predict oppositionality in cases and controls. A significant prediction could only be obtained for ADHD children with the EE sub-measure of high warmth predicting low oppositionality ratings  = 4.45, p = .039).Fifty nine tapes from parents of ADHD children, and 58 tapes from parents of control children could be scored. An ANOVA revealed significant differences in EE ratings with parents of ADHD children showing more EE than those of control parents  = 2.14, p = .146. Thus no general differences between ADHD and control children in cortisol level at baseline needed to be taken into account in the analysis. A multivariate analysis with repeated measures compared cortisol responses over time for both groups of children and the two conditions (negative vs. positive). There was a significant three way interaction  = 2.04, p = .009, η2 = .035). Adding oppositional ratings as a covariate removed the significant difference in cortisol response  = .479, p = .751, η2 = .009), whereas controlling for age  = 2.70, p = .034, η2 = .093) and gender  = 0.226, p = .0635, η2 = .001) did not. As can be seen in figure First baseline cortisol levels T1) were compared that revealed no differences between cases and controls: ADHD: mean = .182, SD = .098; controls: mean = .210, SD = .117;  were comR .433, p < .001). A stress-index that reflects decreases in cortisol levels from baseline (T1) to the final measure (T5) was used as the mediator variable. This was based on cortisol responses in the control group, since they showed the expected circadian decrease in cortisol response across the day with levels decreasing by 86.5% from T1 to T5 averaged over both conditions. Relative to this decreases in cortisol levels for ADHD children differed according to condition with children in the positive condition showing a decrease of 69%, and children in the negative condition one of only 12.7%. Figure To test the mediator model, Conners' ratings of oppositional behavior were used as a measure of OPB , as was the path between the putative mediator (cortisol stress response) and the dependent variable (conduct problems) . The significant path between positive comments and OPB had already been established. Together these associations established pre-requirements for testing mediation . This was achieved in a second step when the significance of the path between EE and OPB became reduced in significance when the putative mediator, stress response index was added to the regression model . A Sobel-test was significant  confirming partial mediation of the link between EE and OPB by stress response.For all children the path between EE (positive comments) and cortisol stress index (putative mediator) was significant . Control children and ADHD children in the positive control condition on the other hand did show a decrease in cortisol over time as did control children in the negative condition. This is in line with the findings by Hooley et al.  who onlyFamily adversity, which can accompany ADHD, is related to higher and less-regulated cortisol activity in school-aged children and adolescents ,58. ChilIn agreement with our mediation hypothesis (see above), we demonstrated that positive EE were significantly linked to the psychosocial stress response which in turn attenuated the direct path between EE and oppositionality. Our results support the important role of positive/warm interactions between parent and child and its effect on oppositional behavior. Since we were able to show this for cases and controls, positive parenting might be a generally protective parenting factor. However, it would be very interesting to replicate findings in a larger sample with separate analyses for ADHD cases and healthy controls. High psychosocial stress on the other hand, as shown experimentally, results in increases of the cortisol response and the tension felt. This in turn might lead to feelings of stress/anger that are expressed in oppositional behavior as described in behavioral models on ADHD and comorbid OPB . Since tThe power analysis prior to testing showed that our sample lacked five participants for optimal sample size. A post-hoc power analysis with the given sample size and 5 repeated measures between 2 groups established a satisfying power of .94 with Lambda = 12.81, F = 3.81, α = .05, f = 0.25. Thus interpretation of results should not be overly biased.For ethical reasons, we were not able to obtain blood samples from the participating families. Due to this, we were unable to assess the critical ACTH component of the HPA-axis. We also did not measure other stress variables such as heart rate or skin conductance response that could have confirmed the cortisol stress responses.Since children with ADHD significantly differed from healthy control children in the Conners' subscale anxious-shy, possible influences on cortisol response had to be taken into account, even though children with positive screenings of internalizing disorders were not included in the study. We collapsed the parent and teacher ratings of the Conners' subscale anxious-shy into one measure and entered this as a covariate in an ANOVA with baseline cortisol as the dependent variable. Anxiousness did not influence levels of baseline cortisol significantly  = 0.100, p .752), though assessment of comorbid disorders on HPA-axis should be addressed in future studies on this topic to further confirm this result.The sample in this study consisted of males and females, though it was predominantly male, representing the four to one prevalence of males to females in populations at large -68. GendThe age range in this sample was fairly large. It is well known that ADHD symptoms change over time, and for children reaching adolescence a reduction in impulsive/hyperactive behavior is often found . But wheOppositional behavior was solely assessed with the Conners Rating Scales. A more thorough assessment of this comorbid condition, especially with respect to the differentiation between ODD and CD might contribute to more specific results.EE were assessed with the short FMSS and not the original Camberwell Family Interview (CFI). Assessment of EE with the CFI takes approximately one to two hours followed by three to four hours rating. Assessment and rating of EE with the FMSS is much faster and correspondence between CFI-EE ratings and those from the FMSS have proven to be highly satisfactory , that thPositive and negative comments were not subjected to qualitative analysis. But since cortisol response of the ADHD children in the positive condition was so akin to that of the controls, we were able to show that ADHD children and controls respond similar to positive feedback and differently to negative feedback. The qualitative difference in negative feedback, that is highly likely, is reflected in the significant differences in high EE ratings by ADHD parents.The cross-sectional study design did not allow us to determine the direction of effects. Future studies should report path models that show the structural relations between the variables analysed.As shown in this and several other studies, parental high EE is a highly salient psychosocial stressor and proves to be relevant for comorbid OPB in ADHD patients. Approaches focusing on the reduction of parental hostility and the enhancement of warmth should be a target for therapeutic interventions to reduce or even prevent comorbid disorders such as OPB. Even though most behavior therapy programs include sessions on positive parent-child interactions their premises need to be further explored and might lead to an improvement of behavioral therapy elements. Furthermore, cortisol levels might serve as a relevant indicator for therapeutic success. Children with disruptive behaviors and low basal cortisol levels had a better response to intervention by parent training as assessed by changes in cortisol levels and disruptive behavior scores .th version; EE: Expressed Emotion; FMSS: Five Minute Speech Sample; HPA: hypothalamo-pituitary-adrenal axis; ICD-10: International Classification of Diseases, 10th version; ODD: Oppositional Defiant Disorder; PC: Perceived Criticism;ADHD: Attention-deficit/hyperactivity disorder; OPB: Oppositional Behavior; CFI: Camberwell Family Interview; CP/TRS: Conners parent/teacher rating scale; DSM-IV, OPB: Conduct Problems; Diagnostic and statistical Manual of the American Psychiatric Association, 4The authors declare that they have no competing interests.All authors have read and approved the final manuscript. HC planned the study, analyzed the data, and wrote the manuscript. RDO, EJSB, and LP co-read the manuscript, and also wrote sections of it, and contributed analyzing strategies. BPH organized the cortisol analyses and advised on their interpretation This work was partly funded by NIMH Grant RO 1MH062873 to S.V. Faraone and by Sarstedt, who supplied the Salivettes for the study. The NIMH and Sarstedt had no further role in the study design; in the collection, analysis and interpretation of data or in the writing of the report.


SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD.Attention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene  score, and the ADHD Rating Scale-IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment.SLC6A2 G1287A polymorphism and response to ADHD treatment.We found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD.Our findings provide evidence for the involvement of the -3081(A/T) polymorphism of  Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder affecting about 3-7% of children with its symptoms of inattention and/or hyperactivity/impulsivity . MethylpIn the prefrontal cortex, where DAT density is low and NET density is higher, it is unlikely that blockade of the DAT is a significant contributor to elevated DA levels in this region. It has been postulated that DA is transported by the NET in the prefrontal cortex, since DA has a higher affinity for the NET as compared with its affinity for the DAT . DAT-selSLC6A2), located on chromosome 16q12.2, is composed of 14 exons spanning 48 kb, predicting a protein of 617 amino acids. It has been suggested as one of the candidate genes associated with ADHD  and hyperactivity/impulsivity subscores  between subjects with and without the T allele Table .SLC6A2 and response to MPH treatment in Korean children and adolescents with ADHD. Those ADHD subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype, although this relative difference does not provide definite conclusion on whether the presence of the T allele is association with a better response or the absence of the T allele is associated with a poorer response, given that even the ADHD patients with the T allele showed only a 61.4% response rate to MPH. In addition, the ADHD subjects with the T allele showed a tendency for more symptom reduction after treatment with MPH than those without the T allele. However, no significant association was found between response to MPH and the SLC6A2 G1287A polymorphism. In a previous study [In this study, we identified a trend for association between the -3081(A/T) polymorphism of us study , those ASLC6A2 -3081(A/T) polymorphism. Kim et al. [SLC6A2 -3081(A/T) polymorphism and ADHD have yielded mixed results, with several studies finding some evidence for association [et al. [SLC6A2 and consequent decrease in transcriptional activity, as reported by Kim et al. [SLC6A2, may be explained by reduced levels of NET within the brain. On the other hand, it is possible that subjects with the -3081(T) allele have their ADHD in tighter relation with the action of NET, and therefore pharmacologically blocking this transporter is associated with relatively better treatment response. Thus, investigating response to treatment and its mechanism of action in terms of molecular and genetic findings might help us to identify more homogeneous subgroups of ADHD [SLC6A2 genetic variation with levels of NE activity in the brain.It is important to understand the potential functional significance of the m et al.  reportedociation ,27, and ociation . Recentlm et al. , may res of ADHD . FurtherADRA2A) or SLC6A2, may have a specific effect as proposed on MPH response [et al. [SLC6A2) were suggestively association with MPH response. On the other hand, in a study conducted by Kooij et al. [SLC6A2 were not associated with MPH response. Here, of note is that the study by Ramoz et al. [SLC6A2 predicted response to another pharmacological agent for ADHD: atomoxetine. In these contexts, our findings demonstrate that the -3081(A/T) polymorphism of SLC6A2 might modulate the effectiveness of MPH treatment on ADHD. To date, this study is the first to examine the association of the SLC6A2 -3081(A/T) polymorphism with MPH response in ADHD. The result of Ramoz et al. [SLC6A2 -3081(A/T) polymorphism constitute a common pathway for the treatment effects of both MPH and atomoxetine.The search for candidate genes associated with ADHD has been largely driven by the understanding that medications for this disorder have drug targets in the catecholamine neurotransmitter systems . Althougresponse ,21,34. Mj et al. , the polz et al.  has demoz et al.  and oursSeveral limitations to this study should be noted. First, this was a naturalistic study, and we did not have a placebo arm in this trial. It is likely that a placebo response in our study group would have decreased the statistical power by reducing the measurement precision of MPH response. However, naturalistic study designs may be valuable to better appreciate the role of genetic factors in routine clinical practice beyond the realm of controlled clinical trials. Second, our study population included all of the subtypes of ADHD, which might have contributed to clinical heterogeneity; the subtypes may have acted as potential confounders of the investigated association. Third, MPH was administered with no control of adherence by investigators. Fourth, we did not control for the two types of MPH products: immediate-release (IR) MPH and sustained-release (SR) MPH. However, we did not find a significant difference in clinical improvement between the ADHD subjects treated with IR MPH and those treated with SR MPH . Lastly, but perhaps most importantly, two titration visits in our study design were probably insufficient, which may have resulted in lower mean daily doses at endpoint, and it might explain the low response rate observed in our results compared to the reported average response rate of approximately 75% in controlled outpatient stimulant trials .SLC6A2 might be involved in the modulation of the effectiveness of MPH treatment in ADHD. Further pharmacogenetic investigations should expand the focus to include other functional polymorphisms of the SLC6A2, given the increased use of noradrenergic drugs in the treatment of ADHD symptoms [vs. poor response to drug treatment for ADHD.In conclusion, our data suggest that the -3081(A/T) polymorphism of symptoms , in ordeThe authors declare that they have no competing interests.BNK, JWK, SCC and HJY designed the study and participated in data collection. BNK, JWK and SBH analyzed the data, interpreted the results, and drafted the manuscript. SCC and MSS supervised the study. All authors read and approved the final manuscript.