The costs and treatment patterns of attention deficit hyperactivity disorder (ADHD) are subjects of health services research in Germany and worldwide. Previous publications focused mainly on prevalent patients and thus research gaps were identified regarding costs and treatment patterns of incident patients before and after the first diagnosis.Analyses were conducted using claims data obtained from a large German sickness fund (Techniker Krankenkasse). Inclusion criteria consisted of patients with at least two secured outpatient or one inpatient ADHD diagnosis in 2007. Incidence was ensured by defining a baseline period without ADHD-diagnosis in 2006. In addition to diseaserelated cost analyses compared to a control group including age group comparisons, comorbidities, the proportion of multimodal treatment and medication treatment patterns were described.In total, 9083 newly diagnosed ADHD patients were identified ). The mean total cost of ADHD patients during the year after the first diagnosis exceeded the mean total cost of the year before by 976 € (Differencein-Difference-estimator: 1006 €). Our analyses have shown that 10 % of ADHD patients have been treated with multimodal therapy. In addition, 11 % of the investigated ADHD population have received methylphenidate or atomoxetine preceeding the date of diagnosis in the relevant observation period.This study provides important insights into the costs as well as the treatment patterns of incident ADHD patients. ADHD-related costs and medications can be identified prior to the date of the first ADHD diagnosis. Although, multimodal therapy is presented as an optimal treatment option by many international guidelines and experts, its proportion for treatment is low (10 %).Further research is necessary to identify reasons for the low proportion of multimodal therapy and (cost-)effectiveness has to be evaluated in comparison to other treatment options. In addition, ADHD-related costs could be identified before the first diagnosis is documented. The reasons for medication prior to diagnosis have to be further investigated. Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders among children and adolescents. The global prevalence has been reported to be between 3 and 5 % , 2. ADHDIn addition, behavioral treatment is based on occupational therapy and psychotherapy, as well as interventions in school. The aim of behavioral treatment is to improve the coping capabilities of the children. Therefore, patients need to participate in attention- and self-instruction training and coaching to sharpen their social skills , 8.Existing studies in Germany focus on prevalent ADHD patients. This applies to studies focusing on economic analyses , 9–11, aIn addition, there is no information whether prescriptions of methylphenidate or atomoxetine are already occurring before diagnosis. Moreover, this study will analyze whether ergotherapeutic and multimodal treatments were prescribed first, like recommended in the guidelines, or a single medication strategy was applied . FurtherAnonymized claims data from the major German sickness fund “Techniker Krankenkasse” (TK) were available for the years 2006 to 2008. This sickness fund covered approximately 6 million insured people in 2008 who were available for this study and were studied regarding the inclusion criteria . PatientThe comparison of costs before and after the first diagnosis required a follow-up period of 365 days for each individual. Scientific data validation was conducted. Besides the basic demographic information (e.g. age and gender) of the incident ADHD patients, further information on outpatient and inpatient care, drug prescriptions, prescriptions of remedies and aids as well as sick leave data were available.The index event is defined as the date of first diagnosis in the observation period for each ADHD patient. Since outpatient diagnoses data is only recorded as a quarter of the year in German claims data and is the most important identification source (98.4 %), the beginning of that quarter was defined as the approximate date of the index event. For instance, the index date of a patient receiving a first-time diagnosis in the second quarter of 2007 was set at 2007-04-01. ADHD patients were compared to a 1:3 matched control group adjusted for age and gender. Therefore, a direct pairwise matching took place with no replacement. The potential control group consists of all TK insured persons with no ADHD diagnosis in the whole study period. Furthermore, the index event for the control group was generated by a random function.Disease- and comorbidity-related costs were identified using an incremental approach and differences by age were studied by age stratification . The costs of the index quarter (quarter of diagnosis) were assigned the year after the index event, because a large number of ADHD-related treatments were initiated in that quarter of initial diagnosis. This method has been applied to avoid overestimation of costs, because the index diagnosis in the outpatient sector could be only identified by quarter. To avoid temporal influences and to approximate disease-related costs when compared with the control group, the difference-in-difference estimator has also been calculated. The difference-in-difference estimator compares the pre- and post-cost difference among the ADHD patients and the control group [Since the comorbidities related to ADHD could have an impact on costs, the most important comorbidities were analyzed. The odds ratio is a proven measure to verify a higher or lower chance for comorbidities in the intervention group , 19. ConAtomoxetine (ATC-Code: N06BA09) and methylphenidate (ATC-Code: N06BA04) were identified by their prescription date of service provision and reported as net values adjusted for co-payments and discounts. Occupational therapy measures were evaluated using the national remedy codes 540*, 541* and 542* in conjunction with the prescription text *Ergo*.U-test following Whitney and Mann for two groups as well as the Kruskal-Wallis test for more than two groups regarding unpaired samples and the Wilcoxon rank-sum test for paired samples has been applied. Significance has been determined at the level of ≤0.05 for all tests.Data management and statistical analyses were performed with Microsoft Office Excel and Access, as well as with SPSS by IBM and SAS 9.3. Because there was no normal distribution for resource utilization and costs identified, the P = 0.000). Age at the first diagnosis averaged around 12.9 years (SD: 10.3). Male patients were diagnosed on average at 11.9 years of age, and female patients at 15.6 years of age. The distribution by age and gender  were identified according to the inclusion criteria. The proportion of male patients was 73 %. The gender distribution varied significantly by age  estimator of the mean total costs was 1006 €. Furthermore, it can be seen that 41 % (411€) of costs can be explained by the difference in costs for ambulatory services Table . In contTable The odds ratio for the indication of injury, poisoning, and certain other consequences of external causes for the ADHD group compared to the control group after the index date showed a range of 1.9, increasing to 19.6 for the indication of specific developmental disorders of scholastic skills. These analyses have shown a remarkable higher burden of disease for ADHD patients Table .Table 4CAnalyzing medication with methylphenidate, it became apparent that 846 (9.3 %)  patients received this agent in both periods of observation (before and after the index event). Furthermore, prescriptions of methylphenidate and atomoxetine had already occurred prior to the initial diagnosis. Thus, 3581 ADHD patients (39.4 %)  received treatment with methylphenidate in the year following the index event, compared to 917 persons (10.1 %)  in the year before. The proportion of patients with prescriptions of both agents increased from 0.34 % before the index date to 2.2 % after the index date.Occupational therapy is an essential element in ADHD-treatment. 28.5 % of patients (2590 patients) were treated with occupational therapy after the index event (before: 18.1 % (1641 patients)). Within the first year following the index event, 9.6 % % of patients obtained multimodal therapy  were treated with this option after the index date and 902 (3.3 %) before the index date.The mean age of those patients receiving occupational therapy after the index date was 8.3 years (SD: 4.0), which is 6.4 years lower than the mean of the remaining patients. This indicates a special application of occupational therapy for younger patients.The objective of this study was to provide real-life information on costs and medication treatment patterns before and after the first diagnosis in the observation period was coded. Costs of 1006 € were identified in the control group approach (difference-in-difference). In addition, prescription prevalence for methylphenidate were calculated to be 39.4 % respectively, while prescription prevalence was lower for atomoxetine (4.2 %). This is in accordance with the German AWMF-guideline, which denotes methylphenidate as the first-line medication in ADHD [There was a recent published study on prevalent ADHD patients. Therefore, a comparison of prevalent and incident patients is possible . If a paThese results have also to be discussed in the context of the international existing literature, even if the comparability of country-specific results is limited due to differences in the treatment and reimbursement structure of different health care systems.Ray at al.  reportedAge at first diagnosis averaged around 12.9 years and did not correspond to the ICD-10 criteria, which states that the disorder should have occurred prior to six years of age . A reasoA large range for comorbidities can be found in the literature related to ADHD. Kessler et al.  computedWithin the observation period, the age at first diagnosis for those who received occupational therapy was about six years lower than for those patients who did not get occupational therapy. A methylphenidate prescription for children under six is only granted under exceptional circumstances. This further strengthens the importance of behavioral treatments for this age group . The mulThis study provides important insights into the treatment patterns and the costs of incident ADHD patients in Germany. However, some limitations have to be mentioned in the context of claims data analyses. Although the TK operates nationwide, there could be some limitations regarding representativeness. As this sickness fund was established for architects, engineers and technicians and the free choice of the sickness funds is only possible since 1996, there could be a bias in terms of e.g. social status . In addiIn addition, the use of methylphenidate is approved for variant indications. Methylphenidate is licensed for the indication of narcolepsy under the trade name Ritalin . HoweverMoreover, there are further limitations in the context of linking occupational therapy with diagnoses. It was barely possible to identify occupational therapy in association with psychic or motoric disorders. However, an assignment to ADHD was not feasible because of the lack of association with treatment and diagnoses in German claims data. However, a higher utilization of occupational treatment could be identified due to the control group approach as a valid measure. A comprehensive demand for evaluation is postulated in the field of occupational and multimodal treatments.In summary, ADHD patients reveal higher resource utilization compared to a control group, even prior to the diagnosis. This became recognizable by the higher costs in the year before diagnosis compared with the control group as well as by the higher usage of methylphenidate and atomoxetine. Therefore, the reasons for medication prior to diagnosis have to be further investigated. Although, multimodal therapy is presented as an optimal treatment option by many international guidelines and experts, its proportion for treatment is low (10 %). Additional research concerning the effectiveness of occupational therapy and multimodal treatments in the context of ADHD incidence has to be performed. Behavioral and multimodal treatments for ADHD as a whole need a health economic evaluation.


Inattention and distractibility are core symptoms of attention deficit hyperactivity disorder (ADHD). Still the neuronal organization is largely unknown. Previously we studied the electrophysiological activity of a distinct neuronal network—the retina—and found no change in stimulus-driven neural activity in patients with ADHD. However there is growing evidence for an elevated non stimulus-driven neural activity, or neuronal background noise, as underlying pathophysiological correlate. To further examine the biological bases that might underlie ADHD and problems with inattention, we performed a new analysis to test the hypothesis of an elevated background noise as underlying neuronal correlate for ADHD and problems with inattention in humans. A direct measure of background noise in patients with ADHD has not been described yet.The retinal background noise was assessed based on pattern electroretinogram (PERG) data in 20 unmedicated ADHD patients and 20 healthy controls. The PERG is an electrophysiological measure for retinal ganglion cell function. ADHD severity was assessed by interview and questionnaire.Noise amplitude was significantly higher (138%) in patients with ADHD compared to the control group (p = 0.0047). Noise amplitude correlated significantly with psychometric measures for ADHD (CAARS) especially inattention .The data provide evidence that an elevated background noise is associated with symptoms of inattention in ADHD and support the use of therapeutic interventions that reduce noise and distraction in patients with ADHD. Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in children and adolescents 8–12%) with a high persistence into adulthood (4–10%)2% with a–7. MedicFrom a functional viewpoint, a reduction in noise is proposed to lead to a decrease of irrelevant information processing and a reduction in distractibility ,9,15. HoOne approach to objectively assess noise in humans and animals is the assessment of the pattern electroretinogram (PERG) evoked by phase-reversing checkerboard stimuli. It offers an easy, direct access to the neuronal network of the retina, which receives minimal influence from higher cortical regions and provides information on early signal processing. The PERG is an objective electrophysiological response, recorded at the cornea in response to visual pattern stimulation ,17. It mThe visual system is a prominent candidate in exploring neurobiological processes underlying attention –22. For The research protocol was approved by the ethics board of the Albert-Ludwigs-Universität Freiburg. Written informed consent was obtained from all participants after the study was fully explained to them.The PERG recordings were conducted at the Eye Center of the University Medical Center of Freiburg. Twenty unmedicated patients with ADHD  were identified at the ADHD program of the Department of Psychiatry and Psychotherapy of the University Hospital of Freiburg . The popThe Freiburg University Center is one of only a few national centers for the diagnosis of developmental disorders in adulthood . The diaParticipants met the DSM-IV criteria for ADHD, classified as either ADHD of the combined or predominantly inattentive type. We excluded all other first axis, major psychiatric disorders, developmental disorders like autism spectrum disorder (ASD) or other neurological, ophthalmological, or medical conditions, except for correctable refractive errors. Senior consultant psychiatrists  assessed the ADHD diagnosis on the basis of a detailed semi-structured as well as structured psychiatric interview  and specifically detailed developmental history following recommendation of respective NICE guidelines for the diagnosis of ADHD and ASD in adulthood–33.Furthermore, the ADHD Diagnostic Checklist corresponding to the DSM-IV-criteria for ADHD adapted for the special needs for adults, as proposed by the German Medical Association (ADHD Diagnostic Checklist), was also carried out,32,34. T2. Our patients were refracted as necessary for the observation distance. To ensure appropriate fixation and accommodation, they reported digits that appeared in random intervals in place of the fixation target.For stimulation, recording, and analysis, we used the EP2000 system . In a diTo evoke the PERG, a sequence of five checkerboard stimuli with a check size of 0.8°, contrast-reversing at 12.5 reversals per second, was presented with Michelson contrasts of 3.2%, 7.3%, 16.2%, 36%, and 80%. Each contrast level was presented for 10 s, and then the next contrast was applied, finally returning to the first contrast level. This interleaved sequence was presented until 80 artefact-free trials per contrast  were accumulated. The interleaved blocking ensured that any sequential effects  were distributed equally across all contrast values. This protocol was repeated once, and further analysis was based on the vector average of each pair of recordings.The PERG response was recorded simultaneously from both eyes using DTL electrodes  placed aThe signals were amplified, filtered (first order 0.5–100 Hz), and digitized at 1 kHz with a 16-bit resolution. To prevent temporal aliasing, all timing  was related to the stimulus monitor frame rate ,42. The Offline, all traces were first detrended (trend mainly remaining from blink excursions) by calculating a linear regression along the trace and subtracting it (to avoid sawtooth artifacts mimicking background noise) ,42. ThenIn patients with ADHD background noise is markedly (138%) and significantly higher than in the control group (p = 0.0047) [control group: mean background noise 0.066±0.005 µV (SEM); patients: mean background noise 0.091±0.006 μV, see To test whether background noise was associated with the severity of ADHD symptoms in subjects, background noise was correlated with the severity of ADHD symptoms obtained with the CAARS.The CAARS scales for inattention , hyperactivity , DSM-IV inattentive symptoms scale , DSM-IV ADHD symptoms total , and ADHD index  correlated significantly with background noise; however, there was no significant correlation with symptoms of impulsivity , problems with self-concept , and DSM-IV hyperactive-impulsive symptoms .In the DSM-IV Checklist, we again found a correlation with the inattentive items , but no significant correlation with the hyperactive items .Separate group comparison  showed no significant correlation in the CAARS or ADHD Diagnostic Checklist.In previous studies we reported an association between severity of depression and retinal contrast gain. Neither the BDI nor subjects age was correlated with background noise.Artefacts are a measure of recording quality and can estimate whether the results might be biased due to aspects such as restlessness, frequent eye movement, or cooperation of subjects. We found that the number of artefacts did not differ significantly between the two groups. In fact, a slightly greater number of artefacts were found among the control group, with a mean of 115.9 compared to 102.1 in the patients group .This study provides evidence for an elevated retinal noise in ADHD. Background noise derived from PERG was higher in ADHD patients than in the control group and correlated with measures of inattention. The retina is a distinct neuronal network without immediate top-down regulation from higher cortical regions. Here, an elevated background noise suggests a compromised neuronal information processing and could explain why patients with ADHD are easily distracted.1(DRD1) [Our results support the hypothesis of an increased background noise as the underlying pathophysiological mechanism in ADHD ,46. Cons1(DRD1) ,4. In li1(DRD1) ,51,52.The positive correlation of background noise with the ADHD index and the DSM-IV ADHD symptoms total score also supports the hypothesis that an increased background noise is consistent with ADHD. The ADHD index discriminates adults who are likely to be diagnosed with ADHD, while the DSM-IV ADHD symptoms total summarizes the number of DSM-IV symptoms of a subject. Some authors suggest that these two scales distinguish individuals with clinical levels of ADHD symptoms, irrespective of whether they have been diagnosed before . The assFurthermore, in our study, background noise significantly correlated even stronger with symptoms of inattention (CAARS: DSM-IV inattentive symptoms and inattention problems) , therebyInterestingly, retinal signal processing is known to be modulated by dopamine (DRD1 and DRD2 pathway),57. For Our finding of an elevated retina noise and the association with inattention may have clinical relevance. While the retina is a very early stage in sensory signal processing, bottleneck alterations there could already have important consequences for attention and distractibility. The involvement of the retina in ADHD supports the use of interventions that reduce distractibility or enhance the salience of tasks . IntervePatients with ADHD are hyperactive and the elevated background noise could be a result of motor activity. However, this is unlikely here since elevated motor activity would result in an increase of artefacts. The artefacts did not differ between the two groups; on the contrary, the number was even lower in the ADHD group. Some additional limitations have to be addressed. Is it possible that patients with ADHD could not perform the task due to problems with their attention? This is not likely since the confounding effect of attention was minimized using an electrophysiological measure that is largely independent of attentional processes. Subjects basically had to watch a computer screen with checkerboard patterns of different contrasts. We ensured that participants cooperated, fixated, and focused by asking them to read out randomly presented digits from the screen center which was performed well by both patient and the control groups. We did not find a correlation of our measures of retinal noise with DSM-IV hyperactivity, self-concept or impulsivity scores in the CAARS, which could indicate either that the CAARS scores were low so the sensitivity for a correlation was not given or the pathophysiology underlying hyperactivity and impulsivity is not represented by physiological alterations at the retinal level, respectively is of different origin.There was no significant correlation between CAARS scores and background noise in the separate group analysis (ADHD or controls only). This study shows an elevated background noise in patients with ADHD compared to controls. Our findings and that of other studies suggest that an elevated background noise might be an important pathophysiological mechanism underlying problems with inattention and distraction in ADHD which can be accessed at the level of the retina.


The current paper presents an analysis of the NICE guidelines on depression and attention deficit hyperactivity disorder (ADHD) from the perspective of the philosophy of science, guided particularly by Foucault's notion of the symbiosis of knowledge and power. It examines how data that challenged the orthodox position on the validity and drug treatment of these conditions was managed in the process of guideline development. The depression guideline briefly considered the complexity and heterogeneity of depression, and numerous methodological problems with evaluating treatments, including antidepressants. However, the guideline recommendations made no reference to these issues and ignored evidence that questioned the analysis of antidepressant trials. The guideline on ADHD reviewed validity, but did not consider evidence from the critical literature, and overlooked inconsistencies in the data. The guideline identified that drug trials have shown no long-term benefit in ADHD, but still recommended treatment with stimulant drugs for children with severe symptoms and for all adults claiming consensus for this position. Both guidelines demonstrate how contradictory data are managed so as not to jeopardise the currently predominant view that ADHD and depression are valid and un-contentious medical conditions that should be treated with drugs. The subjective nature of guideline formation that is revealed illustrates Foucault's suggestion that the authority of medicine operates to promote a technological view of the nature of certain human problems, which in turn strengthens medical hegemony over these areas. Since then, NICE guidelines have become internationally influential and, unless appropriately contested, are often viewed as representing the gold standard of medical practice.The NICE guideline on depression was first published in 2004 and updated in 2009 , 2009. IThe increasing popularity of clinical guidelines reflects political changes in western systems of healthcare delivery, and the changing nature of professional power . OrganisPhilosophers of science and knowledge have long questioned the idea of objective, value-free, scientific knowledge that is embodied in clinical guidelines. They have pointed out that knowledge is shaped by local and historical circumstances , and thaThe current paper presents a systematic examination of the process of guideline formation, using the guideline documents themselves, and some direct process data (see below). The analysis focuses on how NICE managed information that contradicted or challenged the currently predominant view that depression and ADHD are valid concepts and that the disorders they represent can be successfully treated with drugs. The analysis illustrates the way that psychiatric knowledge is shaped more by human interests and power dynamics than objective data.From its inception, NICE offered that any interested groups or organisations could become registered ‘stakeholders’. Stakeholder groups are invited to comment on a draft of guidelines relevant to their interests prepared by a Guidelines Development Group, made up of invited experts and service user representatives. The Guideline Development Group considers these comments during the process of formulating the final draft of the guidelines and makes a detailed response to the stakeholders about the comments submitted.2 One of the authors (ST) also participated in a ‘conference of experts’, organised by the NICE Guideline Development Group to inform the development of the ADHD guideline. The Full guideline itself, as well as the draft version, can be also viewed as process data, since they describe what evidence was selected for consideration by the Guideline Development Group, what evidence was omitted, and how this evidence was managed in relation to the final recommendations. The current paper is based on an in-depth analysis of the guideline documents, the NICE response to the Critical Psychiatry Network's contributions (hereafter referred to as the stakeholder contributions), and the experience of the second author during and after the guideline conference.The authors of the current paper were involved in commenting on drafts of the depression and ADHD guidelines on behalf of the Critical Psychiatry Network, a registered stakeholder.In sections dealing with the concept of depression, the NICE guideline acknowledges that there are some difficulties in defining the term, and in categorising severity, but these difficulties and their implications are not examined in depth and do not influence subsequent discussions or recommendations. The presence of some discussion, however cursory, allows the guideline to claim that the question of validity has been covered, without jeopardising the subsequent analysis and conclusions.The introduction of the guideline states that ‘Distinguishing the mood changes between major depression and those occurring “normally” remains problematic’ , 14 and there is increasing concern that ‘depression’ may be too heterogeneous in biological, psychological and social terms to enable clarity on which specific interventions will be effective – for which problem, for which person, and in which context. (19)Despite the uncertainty expressed in these quotations, the guideline did not consider any critical literature on the validity of the concept of depression, despite references being provided in the stakeholder submissions .The Guideline recommendations categorise depression into ‘mild’, ‘moderate’ and ‘severe,’ based on the tenth edition of the International Classification of Disease (ICD-10)  and treait is doubtful whether the severity of a depressive illness can realistically be captured in a single symptom count, although there is some evidence for this. , 19The paper it cites as evidence in this sentence shows that the number of symptoms does not correlate with the severity of a depressive disorder when severity is measured by non-symptom count approaches such as measures of global clinical state and functioning .In a similar approach, NICE discusses the methodological problems of antidepressant trials in the Full Guideline, discussing at some length publication bias, infringement of the double blind, and uncertainty about the generalisability of trial subjects. The guideline then moves on without probing too far into the implications of these problems. These, and other issues relating to methodological problems in trials that were raised in the stakeholder submission, were either not commented on or given a brief and superficial response in the guideline development group's reply to comments submitted for the first version of the Guideline produced in 2004. No response was ever made to comments made in the stakeholder submission for the revised Depression guideline published in 2009. Hence, NICE did not explain why studies that showed that early detection of depression did not improve outcome, and well-known negative antidepressant studies and meta-analyses were not cited, and it did not engage with comments made about the inconsistency of its claims about severity and antidepressant response. These failures to include significant material allowed NICE to present clear and unambiguous recommendations on drug treatment.The most important point made in the stakeholder submission on the draft guidelines concerned the presentation of data from the meta-analysis of placebo controlled trials of SSRI antidepressants conducted by NICE, in particular the use of categorical data. In this analysis, reduction in depression rating scale scores over the course of treatment were slightly greater in people taking SSRIs, but the guideline authors considered that, although statistically significant, the differences were so small that they were ‘unlikely to be of clinical significance’ , 169. ThIn a similar manner, whilst NICE admits that patients with mild depression should be treated without antidepressants, it recommends that those with moderate or severe depression should receive medication. The Full guideline, however, admitted that there is little evidence with which to relate antidepressant effects to severity levels , 163, anThe Guideline Development Group that produced the NICE guidelines on ADHD was made up of academic psychiatrists and others known to be strident advocates of the concept of ADHD, including the foremost exponent of the diagnosis of ‘adult ADHD’ in the United Kingdom. Much of the research cited in the guideline was conducted by a small number of researchers including members of the Guideline Development Group and their associates and several members of the group declared financial interests involving pharmaceutical companies.During the early stages of guideline development, what was then referred to as a ‘conference of experts’ was set, at which one of the authors of this paper, was asked to participate (ST). ST stated, prior to accepting the invitation that he feared that he would be used as the ‘token’ critic to enable NICE to state that they had represented a cross-section of professional opinion, and was reassured that this would not be the case. During the meeting, which was supposed to focus on the validity of the diagnosis, ST presented a detailed argument, that the neurodevelopmental model of ADHD could not be supported by existing evidence. The questions from the guideline development group following this presentation, did not focus on any of the content of the presentation, but instead was dominated by repetitive questioning about whether or not ST had ever prescribed stimulants. Despite ST providing only qualified assent to this question, in that he pointed out that he had not initiated a prescription of stimulants for a new patient for many years, the Full Guideline described the meeting as a ‘consensus conference’ and the report emphasises repeatedly the agreement and ‘unanimity’ between participants, particularly with regard to the Guideline recommendation for the drug treatment of children with severe symptoms , 119. AsAs for depression, the recommendations section of the Full Guideline and the Quick Reference Guide on ADHD make no reference to there being any concern or controversy over the concept of ADHD. However, the text of the Full Guideline discusses the issue of validity at length. Although it concludes that ADHD is an easily identifiable, discrete disorder that responds to specific treatments, it acknowledges that:The use of the diagnosis of ADHD has been the subject of considerable controversy and debate and the diagnosis itself has varied across time and place as diagnostic systems have evolved. Despite this caveat, the Full Guideline includes no references drawn from authors who are critical of the concept of ADHD, and issues such as the cross-cultural validity, gender disparity, and social class distribution of ADHD were largely ignored. Moreover, there is no agreement about what level of symptoms could be expected as a baseline in children or adults without the disorder. Despite this, even by its own standards, the guideline provides little evidence that ADHD satisfies the validity criteria specified, and, like the depression guideline, it glosses over apparent problems and often fails to mention contradictory data.The guideline specifies the following validity criteria: that the symptoms of ADHD  should cluster together and be distinguishable from normal variation and other psychiatric conditions; that symptoms are associated with significant clinical or social impairments; that symptoms are associated with a characteristic temporal pattern or outcome and that there is ‘consistent’ evidence of genetic, environmental or neurobiological risk factors.The guideline development group reviewed studies using factor analysis and latent class analysis of symptoms of behavioural disorders in children. The majority of studies using factor analysis found that ADHD symptoms ‘represent separate but correlated factors from oppositional and conduct problems’ , 102. HoThe Guideline concludes that it is also difficult to distinguish ADHD from the normal spectrum of behaviour, since there is much overlap between people with and without the diagnosis in terms of symptoms or behaviours: ‘Most analytic approaches are unable to make a clear distinction between the diagnosis of ADHD and the continuous distribution of ADHD symptoms in the general population’ , 104.symptoms, rather than the diagnosis, are associated with impairments. Since the diagnostic criteria for ADHD require the presence of ‘significant levels of impairment’ . However, it failed to cite any evidence that , 107. Hoairment’ , many moairment’ .The Guideline emphasises the stability of symptoms throughout childhood as evidence that the disorder has a characteristic pattern and outcome. However, three of the four studies cited show only ‘moderate’ stability, which is represented, for example, by a correlation of only 0.5 between symptoms at different ages .As far as aetiological factors are concerned, NICE follows prominent academics in the world of child psychiatry, by implicitly referring to ADHD as a ‘neurodevelopmental disorder’ (i.e. a disorder of the development of the nervous system), suggesting for example, that ‘… ADHD may be viewed as one component of a general propensity to neurodevelopmental problems’ , 103. Ge‘Nevertheless, the disorder remains one that is defined at a behavioural level, and its presence does not imply a neurological disease’ , 15 and In any case, the research cited only provides evidence of a weak genetic link, and no data are presented that could exclude confounding factors, or confirm the specificity of the associations described. The review of genetic studies concludes that: ‘As with all other types of risk factors associated with ADHD, the individual genetic variants associated with the disorder are neither sufficient nor necessary to cause it, but contribute a small increase to the overall risk for ADHD’ (111). The Guideline Development Group did not consider criticisms of the genetic studies, however, including possible confounding with co-morbid conditions such as learning disability and the fallacy of the ‘Equal Environment Assumption’ in twin studies  .NICE notes the lack of consistency found in neuroimaging studies, which suggests that numerous brain regions may be implicated, with little replication of regions between studies. The guidelines also notes that ‘it was not possible to include or exclude the role of medication in the observed changes to brain volume and structure’ , 110, buThe guideline also concludes that there is a positive association with a large number of familial and environmental adversity indicators, including prenatal maternal stress, early deprivation, maltreatment, sexual abuse, large family size, paternal criminality, maternal mental disorder, foster care placement, and some dietary components. Again, however, no evidence is offered that any of these factors are specific to ADHD, as opposed to say conduct disorder, and the large number of associated factors suggests that no specific cause has actually been identified. If everything causes ADHD, then in fact we know nothing about what causes it.Since adult ADHD is a recent construct, NICE might be expected to consider the issue of validity particularly closely. Instead, the Guideline accepts the diagnosis with little question. First, the guideline cites one meta-analysis suggesting that 15% of children with ADHD continued to fulfil diagnostic criteria at age 25 . It contThe profile of symptoms may alter with a relative persistence of inattentive symptoms compared with hyperactive-impulsive symptoms; however the evidence base for this conclusion is poor and based on the analysis of developmentally inappropriate measures of hyperactivity-impulsivity in adults. The GDG (guideline development group) concluded that there is currently insufficient evidence to warrant a different diagnostic concept in childhood and in adulthood. , 108lack of evidence that the concept of adult ADHD is different to childhood ADHD, offering no positive evidence of direct links between the two conditions. There is also little acknowledgement that ADHD has its origins as a childhood disorder and that concepts such as impulsivity and hyperactivity were originally defined as developmental problems, their applicability to adults remaining uncertain.Somewhat unusually, this, the main section supporting the validity of adult ADHD, does so on the basis of a The only criterion of validity that was examined in relation to adult ADHD was whether it can be distinguished from other common adult psychiatric disorders. The Guideline notes the overlap between symptoms suggested to be characteristic of adult ADHD and symptoms of various personality disorders . No evidIn common with the depression guideline, and with other systematic reviews of ADHD medication treatment , the NICThe guideline states thatEven the most ardent supporters of non-pharmacological interventions in ADHD recognised the importance of pharmacological treatment in the most severe cases. , 121No reference is provided for this statement, which appears therefore to be based on the guideline development group's representation of the ‘consensus conference’ detailed above.The second reason given in support of using medication as a first line treatment in severe ADHD referred to a paper that reports a re-analysis of data from the largest trial comparing medication and behavioural treatments . This paper concluded that a subgroup of children with more severe ADHD symptoms showed a larger decrease in symptoms with medication than with behaviour therapy . The MTAThe recommendation of the NICE guideline to use medication as a first line treatment for adult ADHD is based on three studies with study duration of 21–45 days . Two of The analysis of two NICE guidelines presented here shows how NICE managed challenges to the validity of the concepts of depression and ADHD, and claims for the efficacy of drug treatment, by acknowledging, but never seriously engaging with, opposing arguments and evidence. This strategy enabled NICE to employ the rhetoric of consultation, while effectively marginalising dissenting views, in order to produce an impression of consensus.NICE's recommendations on the treatment of depression and ADHD make no reference to any problems with the concepts concerned, implying their validity is universally accepted and unproblematic. The depression Guideline, for example, recommends screening certain populations for the presence of depression, which implies a confidence in the diagnosis of depression that is belied by statements in other parts of the Guideline itself. Other than acknowledging that drug treatment of milder disorders is unsupported, recommendations on drug treatment in both Guidelines also failed to reflect the methodological difficulties that were described in other parts of the Guidelines, and the consequent uncertainty of the evidence. Consensus for drug treatment of severe ADHD was claimed without justification and comments that challenged the interpretation of evidence on antidepressants in the depression guideline were ignored.In both depression and childhood ADHD, the guidelines do not recommend drug treatment as a first line in mild cases, but only as a first line treatment in severe, or moderate to severe, cases. However, although the idea that drug treatment is likely to be more effective in more severe conditions has been assumed for many years, little evidence is cited in either guideline to support this supposition. Since the criteria for assessing severity are only loosely defined, have no distinguishing features, and are not used clinically, it is likely that the label ‘severe’ will simply be applied to cases in which drug treatment is the desired outcome of the diagnoser or service user. The fact that by 2010, prescriptions for antidepressants in England had risen by 48% to 43 million since the publication of the NICE guideline in 2004, and that stimulant prescriptions have continued to rise since 2008, supports this notion .The recommendations concerning adult ADHD are perhaps the most remarkable. A sea change in current psychiatric practice is recommended, with encouragement for the use of a controlled drug with a potentially large adult population and where the possible personal and public health implications of this remain unexplored. The case for the validity of the disorder was hardly considered, and the evidence cited in support of drug treatment was slim and contentious.The current analysis focuses on the content and development of the NICE guidelines, and has not looked in detail at underlying motivations and interests. The conclusions of both guidelines support the primacy of a technological, medically-based approach to understanding and treating psychiatric disorders, and as others have described, a complex array of interests are served by the medicalisation of human difficulties . The medThe current analysis of the formation of psychiatric guidelines illustrates the symbiosis between power and knowledge highlighted by Revealing the mechanics of guideline construction, and the difficult task of moulding divergent views and flawed and inconsistent evidence into an authoritative justification of practice, helps to underline the contested nature of psychiatric ‘knowledge’. Further investigation could help to illuminate the diverse interests that are served by the medicalising perspective that the guidelines endorse.


Attention deficit hyperactivity disorder is the most common childhood neurobehavioral disorder with well documented adverse consequences in adolescence and adulthood, yet 60-80% of cases go undiagnosed. Routine screening is not practiced in most pediatric outpatient services and little information exists on factors associated with the condition in developing countries.This was a questionnaire based cross-sectional survey whose primary objective was to determine prevalence of attention deficit hyperactivity disorder (ADHD) symptoms in children aged 6-12 years attending a tertiary care hospital Accidents and Emergency unit. Secondary objectives were to: (i) ascertain if physical injury and poor academic performance were associated with ADHD, (ii) compare diagnostic utility of parent-filled Vanderbilt Assessment Scale (VAS) against Statistical Manual of Mental Disorders-IV (DSM-IV) as the gold reference and (iii) establish if there exists an association between ADHD symptoms cluster and co-morbid conditions.Prevalence of cluster of symptoms consistent with ADHD was 6.3%  in 240 children studied. Those affected were more likely to repeat classes than the asymptomatic . Additionally, 67% of the symptomatic had previously experienced burns and 37% post-traumatic open wounds. The odds of having an injury in the symptomatic was 2.9  compared to the asymptomatic. Using DSM-IV as reference, VAS had a sensitivity of 66.7%  and specificity of 99.0% . Positive predictive value was 83.0%  and negative predictive value 98.0% (CI 95.1-99.1). Oppositional defiant disorder symptoms, anxiety, depression and conduct problems were not significantly associated with ADHD cluster of symptoms.The study found a relatively high prevalence of symptoms associated with ADHD. Symptomatic children experienced poor school performance. These findings support introduction of a policy on routine screening for ADHD in pediatric outpatient service. Positive history of injury and poor academic performance should trigger further evaluation for ADHD. Vanderbilt assessment scale is easier to administer than DSM-IV but has low sensitivity and high specificity that make it inappropriate for screening. It however provides a suitable alternative confirmatory test to determine who among clinically symptomatic patients requires referral to a psychiatrist. Attention deficit hyperactivity disorder (ADHD) is the most common childhood neurobehavioral disorder . AffecteFew studies on ADHD have been done in Africa. Polanczyk et al. reported a worldwide pooled prevalence of ADHD of 5.3%  . The stuADHD is associated with co-morbid conditions such as oppositional defiant disorder (ODD) in 35.2% of the affected, conduct disorders (26%), anxiety disorders (26%) and depression (18%) . ADHD anChildhood behavioral disorders such as ADHD, predict lower scores on academic tests and early termination of education. In a population based study of 700 children, Breslau et al. found attention problems to be the chief predictor of diminished academic achievement relative to expectations on the basis of a child’s cognitive ability. Students with inattention are inefficient learners thus limiting their acquisition of basic skills necessary for higher education .Studies have shown association between ADHD and risk for unintentional injury due to behavioral risk factors such as impulsivity, inattention, risk-taking behavior and carelessness ,13. MediMerrill et al. sought to determine if an association existed between ADHD and occurrence of injuries. Their findings were that “sprains and strains of joints, open wounds of head, neck and trunk, and upper/lower limb, and fractures of the upper/lower limb” were common. The proportion of severe injury such as “fracture of skull, neck and trunk; intracranial injury excluding those with skull fracture; and injuries to nerves and spinal cord” was three times more common in children with ADHD .Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) is the gold standard for diagnosis of ADHD but both parents and clinicians find it complex to use . This maNational Initiative for Children’s Healthcare Quality (NICHQ), in conjunction with the American Academy of Paediatrics (AAP) developed a tool kit for evaluation and management of children with ADHD. This toolkit is designed to be used by general practitioners and paediatricians and contains an initial evaluation form comprising of history, clinical examination and VAS for diagnosis of ADHD . A similThe primary purpose of this study was to determine prevalence of ADHD. The two secondary objectives were to: (i) find out whether there is association between ADHD injuries, academic performance and other co-morbid conditions  and, (ii) evaluate utility of the easier to administer VAS as a screening tool for ADHD in a busy accident and emergency setting.The study was undertaken at the paediatric accidents and emergency (A&E) section of the Aga Khan University Hospital (AKUHN) between March and June 2012. AKUHN is a private, not for profit, tertiary health care facility based in Nairobi, Kenya. Paediatrics A&E offers a 24-hour service provided by paediatric residents and senior house officers under the supervision of paediatric registrars. Approximately 70-80 children of diverse ethnic and racial backgrounds are seen daily with an approximately equal gender distribution. Majority of children present with common acute childhood illnesses like acute respiratory tract infection, gastro-enteritis and bronchial asthma. Thus, our study population for this cross-sectional survey comprised of children with various medical and surgical conditions.Children aged 6-12 years were enrolled provided guardians demonstrated ability to read and write in English. A written signed informed consent was also required from the primary care provider. Children on methylphenidate, antidepressants or behavioral therapy and those with neurological disorders, hearing and visual impairments or need for emergency care were excluded. Those who consented were clinically evaluated and treated for the ailments that brought them to hospital prior to completion of the self-administered study questionnaire.Sample size was estimated at 240 based on estimated ADHD prevalence of 6% reported by Kashala et al.  from a nStudy approval was obtained from the Aga Khan University Hospital Scientific and Ethical Review Committees. Enrolling of children was done after written consent from parents or primary guardians as required by the institutional review board for children under the age of 18 years. It was made clear that recruitment was entirely voluntary and that refusal to participate would not in any way compromise provision of care. Study records were secured in a locked cabinet to safeguard confidentiality.Study was carried out using a two-stage ascertainment procedure. Children were evaluated for eligibility after registration at the reception between 9 am to 8 pm during week days. A maximum of 10 participants were recruited on any given day to minimize burden in the department and to hopefully capture a wider spectrum of medical conditions. Details about the study were explained to the parents by the principal investigator or the research assistant after patients had been seen by the clinician for the presenting problem. Information necessary for DSM-IV classification was obtained from parents who also completed VAS form.Vanderbilt diagnostic parent rating scale has 55 questions divided into two sections comprising of symptoms and performance. The symptoms section contains 47 questions that are divided into various sub-sections as follows: questions 1-18 covers symptoms of ADHD, questions 19-26 oppositional defiant disorder symptoms, questions 27-40 conduct disorders and 41-47 anxiety and depression. Performance section has eight questions that indicate the level of impairment under questions 48-55. School performance, relationships with family and peers and participation in organized activities are considered under this section [Directions for filling out the form require parents to think about the child’s behaviour over a six month period. Additionally, the form has questions on whether patient is on medications. Symptoms scales are rated: never = 0, occasionally = 1, often = 2, very often = 3. Parent is also instructed to circle only one of the numbers on the scale. Similarly, performance scales are rated as: excellent = 1, above average = 2, average = 3, somewhat of a problem = 4, problematic = 5. The parent form contains 55 items that take approximately 10 minutes to complete .Numbers for each section were tallied to meet DSM-IV criteria for diagnosis. For the predominantly inattentive subtype of ADHD, the patient was expected to score either a 2 or 3 in six out of nine questions under 1-9 and score 4 or 5 on the performance questions 48-55. To be categorized under predominantly hyperactive/impulsive subtype of ADHD, the score had to be either a 2 or 3 in six out of nine on questions 10-18 and 4 or 5 on the performance questions 48-55. ADHD combined inattention/hyperactivity required the above criteria on both inattention and hyperactivity [ADHD co-morbid conditions on the form were: ODD had to score a 2 or 3 in four out of eight on questions 19-26 and score 4 or 5 on the performance questions 48-55. Conduct disorder score was 3 out of 14 on questions 27-40 and score 4 or 5 on performance questions 48-55. Anxiety/depression had to obtain 2 or 3 on three out of seven in questions 41-47 and score of 4 or 5 on performance questions 48-55 .The first author (SW) or a pre-trained research assistant explained to parents how to fill out a questionnaire adapted from American Psychiatric Association, Diagnostic and statistical manual of mental disorders , 4th ed.Care providers of study children were requested to complete the risk assessment form with assistance provided as needed. It contained questions about school performance such as repetition of class and average end of term marks which was categorized as; below 25%, 25-50%, 50-75% or above 75%. A grade above 50% was considered as acceptable performance. Only injuries for which medical treatment was sought were considered for inclusion and categorized into burns, fractures and open wounds. Information on causes of injuries was classified under falls, fight, car accident and others. Completion of an assessment form took approximately 15 minutes after which questionnaire was scored and tabulated before providing feedback to parents. A neuro-developmental history was taken from guardians of children who screened positive for ADHD symptoms followed by a comprehensive physical examination. Visual acuity test was done using a Snellen chart and bed side testing for hearing performed using a 512 Hz tuning fork. After addressing any concerns raised by guardians, children who screened positive for ADHD were referred to a psychiatrist for re-assessment and appropriate management at a pre-negotiated subsidized cost.The first author or research assistant explained to parents the importance of getting input from the child’s teacher. Parents were asked to consent and sign a release of information form that was then to be passed on to teachers responsible for documenting school performance feedback. Parents were asked to forward pre-stamped, self-addressed envelopes containing the DSM-IV and Vanderbilt Teacher Assessment (VTA) forms to the class teachers for completion. They were also requested to mail back completed forms to the investigator. A cover note explaining the study to teachers and instructions on how to fill the form, including a completed sample form, was enclosed in the package. The note stated that that the child would be evaluated for an undisclosed medical condition and that teachers were to complete a form on behavioural rating without specifying the actual behavioural condition. Further, they were to sign a confidentiality agreement in order to protect the privacy of the patient. Where responses delayed beyond two weeks, a telephone reminder was sent through the parents.Access to anonymous paper assessment forms and computerized data were limited to the principal investigator and research assistant. Data were entered in Microsoft Excel® and analysis done using STATA® Version 11 (StataCorp). Prevalence of ADHD symptoms was calculated using the number of positive cases as numerator and study population as denominator. Chi square or Fischer’s exact test were used as appropriate to compare categorical variables with P-value below 0.05 considered significant. Wilcoxon test was used for ordinal data. Odds ratios (OR) were used to determine association between ADHD symptoms and categorical variables and 95% confidence interval (CI) to determine precision around individual estimates.A total of 240 patients between age six and twelve years were recruited over a period of four months. Their median age was nine years with an interquartile range of 7-11 years (p = 0.24). There were 15 children found to have symptoms of ADHD using DSM-IV criteria giving a prevalence of 6.3% . The ADHD symptomatic group was further categorized into respective subtypes as follows: hyperactive 7/15, 47.0% , inattentive 3/15, 20.0% , and combined form 5/15, 33.0% .Seven children were described by parents as having inattentive (two), hyperactive (four) and combined forms (one) of ADHD symptoms. As we were unsuccessful in collecting information on social and academic function for most subjects, none was confirmed to have impairment in those aspects hence inability to determine true ADHD prevalence.There was no sex (p = 0.89) difference between children with and without ADHD symptoms Table . Age disTable The study evaluated association between ADHD symptoms and co-morbidities such as oppositional defiant disorder, anxiety, depression and conduct disorders Table . Only onThis study found ADHD symptoms prevalence of 6.3%  among children visiting a busy paediatric accident and emergency unit of a tertiary care private “not-for profit” teaching hospital. Although seven children were described by parents as having ADHD (hyperactivity-impulsivity and inattention) symptoms they had no observed functional impairment hence they did not meet the diagnostic criteria for inclusion as ADHD. Further, the low response rate from teachers made it difficult to determine whether or not there was academic dysfunction attributable to the condition thus limiting our ability to estimate actual prevalence of ADHD. We unfortunately received only six reports back from teachers despite reminders. This meant we had to rely exclusively on parental reports based on observed home behavior. But parents were also expected to recall the history over the past six months which may suffer from recall bias. A combination of these factors could have contributed to underestimate of the true prevalence. The estimate is nevertheless comparable to prevalence of 5.3% and 6% in neighboring Congo and 8% in Nigeria suggesting error may be marginal [Magnitude of prevalence of ADHD is influenced by the criteria used. This type of variation is not unusual as illustrated by Wolraich et al. who encountered a similar inaccuracy in diagnosis when 4323 children were evaluated for ADHD in 10 schools in Tennessee . They foUnlike some other investigators, this study did not observe any gender difference between children with and without symptoms of ADHD. This could be explained by the small sample size filing to detect a true difference if it indeed existed. It could also have been caused by some unidentified seasonal occurrence like preferential referral of girls over the study period. The National Survey of Children’s Health reported a male to female prevalence ratio of 2.5:1 with clinic based populations showing 10:1 . SpencerWe found some association, albeit weak, between past injury, especially burns, and ADHD despite the low power of the study. Whereas a larger sample size is needed to examine this further, Tai et al. prospectively looked at “injury-proneness” of children aged six to eighteen years and found children with ADHD to have a 2-5 fold increase in risk of injury . AdditioA striking observation from our study was the up to 20-fold increase in risk of repeating classes in children with symptoms of ADHD as a manifestation of poor academic performance. This phenomenon should increase index of suspicion for ADHD among health professionals. In a study of a class of 700 by Breslau et al. on impact of early behavior disturbances on academic achievement, students with attention problems were found to be inefficient learners which limited their ability to acquire basic skills necessary for higher education .Unlike other studies, ADHD in our study was not associated with oppositional defiant disorder, anxiety, depression and conduct disorders in this study . This maVAS would clearly not be recommended for ADHD screening in view of the low sensitivity found in this study as many with the condition would be missed out. However, the high specificity and high positive likelihood ratio argue a case for its use in already suspected diagnosis from say, history of poor school performance or injury and suggestive symptoms of ADHD. Testing positive in such patients would then suggest strong need for referral to a psychiatrist for further assessment. Utility of other behavioral scales such as Conner’s Questionnaires and Strength and Difficulties Questionnaire as alternatives to DSM IV need to be further investigated in subsequent studies.Among our initial intentions was to estimate prevalence of ADHD and other commonly associated behavioral conditions. We were however not successful in getting many reports back from school teachers despite reminders hence we could only determine ADHD associated symptoms without demonstrating effects on school performance and relationships with peers at school. Further, we used self- administered questionnaires rather than face-face interview that would have offered better opportunity for clarification on items that could be confusing to the respondent.Our study was also powered to determine prevalence of ADHD symptoms but not co-morbid conditions which would call for a larger sample size. Also, as the study was conducted in a private health facility outpatient department with access limited to some members of the population, generalization should be confined to similar settings.A relatively high prevalence of ADHD symptoms in paediatric accidents and emergency departments justifies introduction of a policy on routine screening of children. Positive history of injury, especially burns, and poor academic performance should prompt clinicians to test for ADHD. Although Vanderbilt assessment scale is not adequately sensitive for use as a screening tool, it demonstrated high specificity and being easier to use in a busy service, would be an alternative to DSM-IV in determining who among the symptomatic to refer for psychiatrist assessment and management.


Investigators at Yale University, New Haven, CT, conducted a meta-analysis to examine the risk of new onset or worsening of tics caused by psychostimulants used in the treatment of children with ADHD. Investigators at Yale University, New Haven, CT, conducted a meta-analysis to examine the risk of new onset or worsening of tics caused by psychostimulants used in the treatment of children with ADHD. A PubMed search identified 22 double-blind, randomized, placebo-controlled studies involving 2,385 children with ADHD. New onset tics or worsening of tic symptoms were reported in 5.7% of the psychostimulant group and in 6.5% of the placebo group. The risk associated with psychostimulant treatment was similar to that observed with placebo (p=.962). The risk was not affected by type of psychostimulant, short or long-acting, dose, duration of treatment, nor by participant age. Crossover studies were associated with a significantly greater risk of tics with psychostimulant use compared to parallel group trials. Meta-analysis of controlled trials does not support an association between new onset or worsening of tics and psychostimulant use. The authors conclude that tics occurring during treatment of ADHD are more likely to be coincidental rather than caused by psychostimulants. The meta-anatysis findings provide strong support for rechallenging children who develop tics that are temporally related to the initiation of psychostimulants. COMMENTARY. Neurologists began to recognize tics as an organic disorder in the 1970s, shortly after the introduction of methylphenidate for the treatment of ADHD . US FDA Notwithstanding the clear evidence from meta-analysis that psychostimulants are innocent as a cause of tics in children with ADHD, the experience of the treating neurologist will often favor contrary conclusions and the avoidance of stimulants in a child who develops tics de novo or has significant worsening of tics when starting stimulants. In an editorial, recommendations for the management of this dilemma are outlined: 1) avoid use of stimulants when other causes of inattention (eg anxiety) are present; 2) explain the rates of tics as an adverse event (20% in children with pre-existing tics and 6% in those who have ADHD without tics); 3) tic occurrence waxes and wanes and may even complicate the introduction of a medication such as clonidine, sometimes used to treat tics .


To investigate attention deficit and hyperactivity disorder (ADHD) drug prescribing in children under 16 years old in the UK between 1992 and 2013.All patients under 16 registered in the Clinical Practice Research Datalink (CPRD) with a minimum of 1 year of observation time and who received at least one prescription of any ADHD drug between 1 January 1992 and 31 December 2013.Trends in prevalence and incidence of use of ADHD drugs in children were calculated between 1995 and 2013 and persistence in new users was estimated.The prevalence of ADHD drug use in children under 16 increased 34-fold overall, rising from 1.5 95% CI (1.1 to 2.0) per 10 000 children in 1995 to 50.7 95% CI (49.2 to 52.1) per 10 000 children in 2008 then stabilising to 51.1 95% CI (49.7 to 52.6) per 10 000 children in 2013. The rate of new users increased eightfold reaching 10.2 95% CI (9.5 to 10.9) per 10 000 children in 2007 then decreasing to 9.1 95% CI (8.5 to 9.7) per 10 000 children in 2013. Although prevalence and incidence increased rather steeply after 1995, this trend seems to halt from 2008 onwards. We identified that 77%, 95% CI (76% to 78%) of children were still under treatment after 1 year and 60% 95% CI (59% to 61%) after 2 years.There was a marked increase in ADHD drug use among children in the UK from 1992 until around 2008, with stable levels of use since then. UK children show relatively long persistence of treatment with ADHD medications compared to other countries. This study is providing an accurate and recent estimate of the patterns of use of attention deficit and hyperactivity disorder drugs in children during the past decades in the UK.The Clinical Practice Research Datalink (CPRD) has major strengths in the study of the use of medication in children. It allows for a recent, large, representative longitudinal cohort of children observing current UK practice.In this study, prescribing issued from general practitioners is described and not actual drug dispensation or consumption by the patient. However, a repeat of the prescription suggests the use of medication in the UK healthcare system.Attention deficit and hyperactivity disorder (ADHD) is an early onset neurodevelopmental disorder combining overactivity and impulsivity with the inability to concentrate  10th edition criteria).The Clinical Practice Research Datalink  is one of the world's largest databases of anonymised longitudinal medical records from primary care since 1987. The database includes data from UK GP practices that provide high quality data on more than five million active patients.11–13All patients registered in the CPRD for at least 1 year in a practice with UTS data and receiving at least one prescription of an ADHD drug (see list below) before the age of 16 between 1 January 1992 and 31 December 2013 were included. For reasons of anonymity, the CPRD database does not give exact date of birth. Only the year (or sometimes the month) of birth is available for all so age estimation is imprecise. Drugs of interest are those included in the British National Formulary chapter 4.4 “CNS stimulants and drugs used for attention deficit disorder”: methylphenidate (methylphenidate ‘immediate release’ and methylphenidate ‘extended release’), atomoxetine, dexamphetamine and modafinil.Yearly prevalence was calculated dividing the number of children under 16 receiving at least one prescription of an ADHD drug during a year by the mid-year counts of children under 16 registered in the database during that year. Children were considered to receive a first prescription if they had a minimum of 12 months without any ADHD drug prescription after registration in the database or were aged below one. Yearly incidence of ADHD drug initiation used the number of children under 16 receiving a first prescription divided by the mid-year counts of children under 16 registered in the database during that year. A Wilcoxon type non-parametric test for trend was computed to investigate prescribing patterns over time.14et al.We also estimated persistence, defined as “the duration of time from initiation to discontinuation of therapy” according to Cramer In our study, 14 748 children under 16 (85% boys) received at least one prescription of an ADHD drug between 1 January 1992 and 31 December 2013. Methylphenidate is by far the most used drug in children with ADHD in the UK accounting for 94% of ADHD prescriptions followed by atomoxetine, dexamfetamine and modafinil .Since only 13 children in the database received ADHD drugs between 1992 and 1995, all further analyses begin in 1995. Between 1995 and 2013, overall prevalence of children receiving ADHD drugs increased 34-fold from 1.5/10 000 children to 50.7/10 000 children in 2008 and then stabilises to 51.1/10 000 children in 2013 . Most ofWe identified 10 566 children (84% boys) who had at least a year of registration in the CPRD before their first prescription of ADHD drug and a first prescription of ADHD drug between 1992 and 2013. Most children (58%) had their first prescription of ADHD medication between the age of 6 and 11 (primary school age), the majority (92%) receiving methylphenidate. The overall incidence of ADHD drug use increased ninefold between 1995 and 2013 from 1.1 to 9.1/10 000 children. However, incidence of new ADHD drugs use decreased slightly from 10.2 in 2007 to 9.1/10 000 in 2013. Again, this pattern is mainly driven by the use of methylphenidate. We can observe how methylphenidate ‘immediate release’ use is slowly substituted by ‘extended release’ methylphenidate after 2002, after its introduction in the UK . AtomoxeIn boys, the incidence of methylphenidate use increased ninefold to reach 16.6/10 000 and decreased to 14.5 in 2013. In girls, the incidence increased ninefold to reach 3.4/10 000 in 2007 and then remained stable at 3.5/10 000 children until 2013 . AlthougSlightly more than 6% (659) of these children received 4123 prescriptions under the licensed age (6 years old in the UK) although 76% were issued between the ages of 5 and 6. Of the 659 children who had a recorded first prescription of an ADHD drug before age six, 245 (37%) had data missing on their month of birth. As a sensitivity analysis, we added 6 months to their age. We observed that 133 were still below six at the date of their first prescription of ADHD drug. Therefore, we can conclude that (659–245+133) 547 (4%) of children in our sample are likely to have been prescribed ADHD medication below age six. While dexamphetamine is licensed for children from 3 years only 52 children of 659 had a first prescription aged under 6, and only two under 3.We identified 1115 (11%) children of 10 566 who had only one ADHD drug prescription and were registered in the database for more than 3 months after this prescription. These patients were not thought to be representative of the majority of children treated for ADHD and were therefore excluded from the retention analysis. This analysis was also split into three groups, under 6, 6–10 and 11–15 years.Our persistence analysis estimated time to the first discontinuation of the treatment (no ADHD drug at least 90 days after their prescription ended). At 1 year, 77% (95% CI 76% to 78%) of children were still taking ADHD drugs decreasing to 60% (59–61%) after 2 years. There was strong evidence that the probability of stopping ADHD treatments within 6 years was higher in older (11 to 15) compared to younger children (6–10), HR=1.87 (1.77 to 1.98) see  and 5.Overall prevalence of ADHD drug prescribing in children increased 34-fold and new prescribing of ADHD drugs increased eightfold between 1995 and 2013. However, the patterns of prevalent and incidence ADHD drug prescribing are changing.Both prevalence and incidence rates started decreasing from 2007 to 2008 and remain stable up to 2013. Methylphenidate was by far the most used drug with 94% of children receiving it. Overall persistence on ADHD medication in children receiving >1 prescription was longer than in some countries. We found 77% (76–78%) of children were still under treatment after 1 year.First, it is important to note that UK rates of ADHD drug prescribing in children are ∼10 times lower than US rates (0.4% UK vs 4.4% in the USA in 2005),19Our analysis highlights two trends in UK ADHD drug prescribing in children. The first a strong increase after 1995, also observed in many other studies. Several studies reported a large increase between 1992 and 2008 in the prevalence of stimulant use in children under 18 in the UK.28Previously, the increase in use of ADHD medications was mainly explained by a better recognition of the issue of the disorders,35et alet al looked at duration of stimulant therapy in the Netherlands from first prescription to the first discontinuation of 180 days. Half of children had stopped their treatment after 20 months for those starting treatment between 1997 and 1999.37Most studies in the literature define the persistence of ADHD drug as time from first prescription to the first discontinuation of 3–6 months. Winterstein The CPRD has major strengths in the study of the use of medication in children.We also acknowledge some weaknesses. First, the CPRD only registers prescriptions issued by the general practitioners and not actual drug dispensation or consumption by the patient, nor does it register prescriptions issued in secondary care by child psychiatrists and paediatricians. However, our intention was to report trends in prescribing patterns, and additionally the extensive repeat prescribing we saw suggests consumption. The lack of accurate information on the exact age of patients for 38% of children with month of birth missing and exact dates for none may have introduced imprecision in the calculation of the number of children that received prescriptions of ADHD drugs under the licensed age (6 years old for atomoxetine and methylphenidate). However, our sensitivity analysis showed that this phenomenon was unlikely to explain the majority of off-label prescriptions. Overall, off-label prescribing of ADHD drug in children under 6 years old appeared to be relatively low.Our analysis of treatment persistence was based on elapsed time between first prescription and a gap of more than 3 months of ADHD drug prescription. It is possible that children with apparent treatment breaks may have received prescriptions from hospital, specialists or other institutions or even had suspended treatment during holidays. In the UK, specialists initiate ADHD prescriptions and continued prescribing and monitoring is typically performed under shared-care arrangements by General Practitioners as recommended by NICE.Among other countries such as the USA, the Netherlands and Germany, the UK shows one of the lowest estimates in ADHD drug prescribing rates in children. Although the prevalence and incidence of ADHD drug use in children have substantially increased during the past two decades, it seems that it may have reached a plateau recently. Looking at overall persistence in prescribing of ADHD drugs, children in the UK show the highest rates of ADHD drug persistence compared to other European countries and the US. These findings may suggest that UK prescribing practice restricts the choice of children receiving ADHD drugs ensuring a better follow-up of these children.Our study indicates a turning point in the patterns of ADHD drug prescribing in children in the UK.


SSB consumption, socio-demographic and lifestyle characteristics of the children, as well as of their mothers’ characteristics during pregnancy, were collected using a questionnaire. Blood lead levels and polymorphisms of two commonly verified dopaminergic-related genes (the D4 dopamine receptor gene DRD4 and the dopamine transporter gene DAT1) were also analyzed. There was a dose-response relationship between SSB consumption and ADHD. After covariates were adjusted, children who consumed SSBs at moderate levels and high levels had 1.36 and 3.69 odds, respectively, of having ADHD, compared with those who did not consume SSBs (p for trend < 0.05). Similar results were obtained when females were excluded. Our findings highlighted the adverse correlation between SSB consumption and ADHD and indicated a dose-response effect even after covariates were adjusted.Attention deficit/hyperactivity disorder (ADHD) is one of the most common childhood neurobehavioral conditions. Evidence of the negative effects of sugar-sweetened beverages (SSBs) on mental health has not been convincing, although a few studies have found an association between high SSB levels and attention problems in children. This study aimed to test the hypothesis that SSB consumption is associated with ADHD among children. Doctor-diagnosed ADHD cases ( In recent years, sugar-sweetened beverages (SSBs) have accounted for 80% of the rise in sugar consumption worldwide. Furthermore, SSBs are the largest single source of added sugar consumption ,2. SSBs Increasing evidence from animal studies clearly indicates that sugar consumption can cause deficits in cognitive and behavioral functions ,10,11,12Taiwan has the highest density of chain bubble tea shops and 24-h convenience stores in the world, and both types of stores sell SSBs ,27. At tADHD is a chronic disease and one of the most common behavioral disorders among children ,35. The Several studies have assessed the association between SSB consumption and childhood ADHD cross-sectionally ,21,25. TThe study protocol was approved by the Taipei Veterans General Hospital and Taipei City Hospital institutional review boards. The project identification codes were 97-01-52A, TCHIRB-1010216 and TCHIRB-1030510 . Written informed consent was obtained from the participants’ parents or guardians. All participants provided their oral or written assent. This study was conducted in accordance with the revised guidelines of the Declaration of Helsinki. We recruited 4- to 15-year-old subjects from outpatient waiting rooms in both hospitals. In this study, the cases were defined as children with ADHD, as identified by board-certificated pediatricians or psychiatrists after at least a three-visit clinical assessment. Children consecutively admitted for initial and follow-up ADHD treatments were also recruited as cases during the study period. Children with neurological deficits or mental retardation were excluded. The ADHD diagnosis was made in accordance with the DSM-IV-TR criteria .We recruited control subjects by randomly selecting normal 4- to 15-year-old children who visited either of the hospitals for reasons unrelated to ADHD during the same study period, and the same exclusion criteria as those applied to the cases were used. We did not attempt to match cases and controls on gender; however, we matched the two groups on age. Controls were screened for the absence of ADHD symptoms by teachers and parent(s), who assessed children’s behaviors in the classroom and at home, respectively, according to the Chinese version of the Swanson, Nolan and Pelham, Fourth Revision (SNAP-IV) questionnaire ,45. The n = 173) and one hundred and fifty-nine normal controls (n = 159). The response rates were 63.6% and 58.9% in the case and control groups, respectively. In examining the association between the intake of SSBs and ADHD, we investigated the following covariates: family factors, maternal lifestyle, participants’ dietary habits, blood lead levels (BLLs) and gene polymorphisms. In this study, participating subjects’ demographic features, dietary habits, mother’s lifestyle during pregnancy, and family history of nervous system diseases were collected via questionnaires. For the measurement of BLLs and analysis of gene polymorphisms, subjects provided a blood  sample during the clinic visit.We recruited a total of three hundred and thirty-two subjects, one hundred and seventy-three ADHD subjects (Lactobacillus casei Shirota [We collected information on each child’s dietary habits and SSB consumption. A trained interviewer administered a 30-min questionnaire to the mother or other caretaker. The average weekly consumption of meat (including poultry and livestock), milk, eggs, fish, shellfish and other types of seafood was gathered for the previous month. The questionnaire also included questions that estimated the average weekly consumption of vegetable  and fruit servings. The weekly serving was calculated by multiplying the daily servings with frequency of consumption per week over the previous month. One serving of meat, fish, shellfish or other types of seafood was approximately 35 g . One cup of milk (approximately 250 mL) and one egg or six quail eggs represented a serving of milk and eggs, respectively. One cup of raw leafy vegetables (approximately the size of the participant’s fist) or a half cup of other vegetables represented a serving of vegetables. One serving of fruit was a medium-sized fruit  or a half cup of chopped fruit. One serving of SSBs contained 600 mL. Parents or caregivers were asked separate questions about how many servings of milk tea, juice or fruit-flavored drinks, Yakult drinks, and other sugar-sweetened drinks the participants normally consumed. The milk tea referenced in this study is also known as boba milk tea, bubble or pearl tea  and is a Shirota . This be Shirota . When quSugar ingested from SSBs was calculated by multiplying the servings by the sugar content in each type of SSB based on a study of the Ministry of Health and Welfare (MOHW) in Taiwan . In addiPeripheral blood was drawn using a syringe or venoclysis needle and then sealed in a heparin-containing vacuum tube and immediately transported at 4 °C to the laboratory. If individuals were not able to supply a blood sample, DNA was extracted from a saliva sample. Saliva was spat into the Saliva DNA Collection and Preservation Kit  and stored at room temperature until analysis. The sample preparation and analysis of BLLs and gene polymorphism are described elsewhere ,54. The Risk factors potentially associated with ADHD were examined. Predictors were chosen according to their association with ADHD in previous studies. The following variables were considered covariates: gender, body weight, child’s age, maternal age at childbirth, gestational age at birth (<37 weeks or ≥37 weeks), parity (primiparous or multiparous) ,56, birtp < 0.05. The covariates related to ADHD at p < 0.05 were controlled in the multivariate analyses. A Kruskal-Wallis test was used to analyze the relationship between ADHD severity and the increased intake of SSBs.SPSS Version 17.0  was used for the statistical analysis. We calculated descriptive statistics based on sample sizes and percentages. Next, we assessed the significance of differences between the case and control groups. A 2-sided nonparametric statistical Mann-Whitney U test was used for consecutive data, and a chi-squared test or Fisher’s exact test was adopted for categorical data when appropriate . Then, wMonte Carlo (MC) simulation, which is a probabilistic analysis, was performed to quantify the theoretical exposure dose range of sugar, AFCs and preservatives. Probability density functions for each parameter were log-normally distributed. Distributions of exposed concentrations and population exposures were estimated by a MC simulation with 5000 replications. Microsoft Excel™ 2010  and Oracle Crystal Ball, Fusion Edition, Release 11.1.2.1.000 software  were used for MC simulation.p-values. Among the 332 participants recruited, 173 were diagnosed with ADHD (148 (85.5%) boys and 25 (14.5%) girls) and 159 were normal controls (91 (57.2%) boys and 68 (42.8%) girls). Male ADHD subjects (n = 148) markedly outnumbered female ADHD participants (n = 25). The age distributions of ADHD and normal controls were similar, with a mean age (±SD) of 8.9 ± 2.0 years and 9.2 ± 2.7 years, respectively (p = 0.31). No significant differences in mean age, body weight, child’s age, gestational age at birth, parity, birth order, maternal age at birth, maternal history of still or dead birth, maternal smoking during pregnancy, or maternal chronic disease during pregnancy were found between ADHD patients and controls. As the mother’s and father’s level of education increased, the risk of ADHD decreased (both p < 0.01). Compared with the control subjects, ADHD cases showed significant associations with family history of nervous system diseases and maternal alcohol consumption during pregnancy. As displayed in p < 0.01). Additionally, mothers with lower education levels consumed more alcohol than those with higher education levels, but this association was marginally significant .p < 0.01). p = 0.04 and p = 0.02, respectively). Control subjects’ intake of vegetables and fruits was significantly higher than that of children with ADHD . No difference was observed in the consumption of eggs, fish and other types of seafood between the two groups.As shown in p < 0.01), representing 102.6% and 89.7% of their DRI, respectively. In addition, the daily caloric intakes of male and female ADHD subjects were significantly higher than those of their counterparts in the control group . We found significant differences between these two groups in energy intake per day attributed to the SSB consumption ; the same observations were achieved for both boys and girls . For children with and without ADHD, the average daily calories obtained from SSBs were 15.9% and 7.8%, respectively. The levels of sugar intake from SSBs of the ADHD group were significantly higher than those of the control group .The levels of sugar intake from SSBs and daily caloric intakes of the ADHD and normal control groups are presented in p for trend < 0.01). The adjusted OR showed that children who consumed 7 or more SSB servings per week had a nearly 4-fold greater odds of having an ADHD diagnosis than the reference group after other variables were taken into account . We observed that children with higher SSB consumption had a greater risk of having ADHD.The crude and adjusted odds ratios (ORs) and their confidence intervals (CIs) from the bivariate analysis and multivariate analysis are shown in n = 25), a sensitivity analysis was performed by excluding females. A logistic regression analysis excluding females suggested that boys with ≥7 servings/week of SSB intake had a greater risk of having an ADHD diagnosis than the reference group (p for trend of 0.06). A marginally significant dose-response relationship was also observed between ADHD and the consumption of SSB for boys after gender, consumption of milk/meat/fruit/vegetables, family history of nervous system diseases, parental education levels, maternal alcohol consumption during pregnancy, and gene polymorphism of DRD4 at rs752306 were controlled. Boys and girls reported similar SSB consumption . Because of the limited number of females with ADHD in this study (ce group . The ORsp < 0.05 and were controlled in the regression model.p = 0.15). No significant difference in BLLs was found between children with and without ADHD . The BLLs were detected in 100% of the participants because LOD was low  and ranged from 0.44 to 4.71 µg/dL. The mean (±SD) of BLLs among the control and ADHD participants was similar , compared with males in the control group . Because SSBs are the principle source of added sugar in diets, SSB consumption may be associated with a concurrent reduction in essential nutrient intake, hypoglycemia and sugar tolerance [Several previous studies have suggested an adverse relationship between sugar consumption  and ADHD ,22,66,67olerance ,73,74. OSSBs often contain other additives that could affect behavior, such as food coloring and preservatives. Some studies have shown an adverse association between AFCs and hyperactivity among children, but other results have been contradictory ,75,76,77The margin of safety (MOS) used for the health risk assessment in Preservatives in children’s food and beverages have also been reported to influence their hyperactive behavior and ADHD symptoms ,76,82,83We found that high maternal and paternal levels of education were associated with a decreased risk of ADHD . This fiThe caloric intakes were 102.6% and 89.7% of the DRI for children with and without ADHD, respectively. In this study, children without ADHD seemed to consume fewer calories than the DRI. Although the potential causal link between diet and ADHD is controversial, nutritional education programs for patients and/or their families should be considered.The World Health Organization (WHO) has proposed that the proportion of daily calories obtained from sugar should be 10% or less . In Taiwp = 0.15). The BLLs in this study were lower than those reported in the other two Taiwanese studies [Low-level lead exposure, even at concentrations much lower than the previous action limit of 10 µg/dL (currently tightened to 5 µg/dL), has been associated with the clinical diagnosis of ADHD in several recent studies ,96,97. W studies ,99. SincThis study has a number of strengths. This is the first case-control study to evaluate the association between SSB consumption and ADHD among children while adjusting for covariates. Moreover, the SNAP-IV questionnaire, a tool with acceptable reliability, was used to screen children suspected to have ADHD. Patients with an ADHD diagnoses were confirmed through extensive evaluations based on the DSM-IV-TR and performed by pediatricians or psychiatrists. This made our confirmation of ADHD cases more stringent than studies that used an interview with a student, parent, or teacher to ascertain ADHD diagnostic status ,25,67. THowever, this study also has limitations. Recall bias of participant characteristics, such as prenatal tobacco and alcohol exposure and family history of nervous diseases, likely impacted our study. We attempted to minimize recall bias by requesting information that did not heavily depend on memory or subjective interpretation, such as parental education level and maternal age at birth. Additionally, because this study did not select participants based on SSB consumption, the likelihood of selection bias was low. Another limitation is that this study did not conduct experiments on the relationship between increased intake of SSBs and the severity of ADHD symptoms. Whether increased intake of SSBs worsens ADHD symptoms or restricted intake of such beverages could reduce ADHD symptoms remain unknown. Moreover, due to quantification difficulties, we did not include the consumption of other foods or processed foods that may contain sugar, AFCs and preservatives, such as cookies, candy and sweets, in the questionnaire. Furthermore, foods with additives, such as monosodium glutamate (MSG), which might increase the risk of having ADHD, were not included in the questionnaire. Considerable clinical and experimental evidence suggests that deficiencies or imbalances in certain micronutrients, such as vitamins A, C, D, B6 and minerals may contribute to ADHD ,101,102.In this case-control study of Taiwanese children, a dose-response relationship was found between SSB intake and ADHD. This association remained unchanged after gender; consumption of milk, meat, fruits, and vegetables; parental education level; maternal alcohol consumption during pregnancy; family history of nervous system disease; and DRD4 genetic variations in rs752306 were controlled. In this case-control study, we have shown an association between SSB consumption and ADHD. However, we cannot demonstrate causality. The consumption of SSBs might be a consequence rather than a cause of ADHD. Future research should explore the direction of and the mechanisms underlying this association.