Little is known about general and family practitioners' (GP/FPs') involvement and confidence in dealing with children with common psychosocial problems and mental health conditions. The aims of this study were to ascertain GP/FPs' preferred level of involvement with, and perceived comfort and skill in dealing with children with behavioral problems, social-emotional difficulties, attention-deficit/hyperactivity disorder (ADHD), and mood disorders; and to identify factors associated with GP/FPs' involvement, comfort and skill.Postal survey of a representative sample of 801 GP/FPs in British Columbia, Canada, which enquired about level of involvement ; ratings of comfort/skill with assessment/diagnosis and management; beliefs regarding psychosocial problems in children; basic demographics; and practice information.2 (1) = 9.0; P < 0.005; and χ2 (1) = 103.9; P < 0.001, respectively). Comfort/skill levels (mean ± s.d) were higher for mood disorders (4.4 ± 1.3) than behavior problems , but not different from social-emotional difficulties (3.8 ± 1.1) or ADHD (3.9 ± 1.3). Taking primary responsibility for a case was consistently related to self-reported comfort/skill with each condition type (34% to 61% of variance across condition types), while comfort/skill ratings for each condition were related to exposure to relevant continuing medical education , and beliefs that these problems are significant and that GP/FPs have a role to play in dealing with them .Surveys were completed by 405 of 629 eligible GP/FPs (64.4%). Over 80% of respondents reported collaborative arrangements with specialists across problem and condition types, although for children with behavior problems or ADHD, more physicians primarily refer (χSupporting GP/FPs in their care for children with common psychosocial and mental health problems should include efforts to bolster their confidence and modify attitudes in relation towards these problems, especially behavior problems and ADHD, possibly within innovative continuing education programs. Clinically significant psychosocial and mental health problems affect up to 20% of children and youth presenting for primary care services , Canada. Our aims were to ascertain the preferred level of involvement of GP/FPs in a range of common psychosocial and mental health problems among children, their perceived comfort and competence in dealing with these problems, and the factors associated with differences in levels of involvement and comfort and skill. We enquired about GP/FPs' involvement with conditions that would be included in both formal diagnostic nomenclature (ADHD and mood disorders), and the more loosely-defined set of conditions described collectively as behavior problems and social-emotional difficulties. The latter terms have been commonly used in large scale surveys of primary care practitioners , and incTo understand the health services context of this study, GP/FPs provide for most of children's primary care needs in BC, with pediatricians and psychiatrists providing mainly consultative services. The costs of 'medically necessary services' for residents of the province are covered under a universal health insurance coverage plan known across Canada as Medicare, although BC residents who earn above a certain level must contribute to annual premiums. Most physicians are paid on a fee-for-service basis through the provincial Medical Services Plan, based on specialty and service-specific fee schedules. Patients have access to any medical practitioner licensed to practice in BC, but specialists require a referral from a family practitioner to obtain specialist rates of pay. There are also mental health clinics throughout the province, most of which require a referral from medical practitioners or other health care professionals. Access to specialized mental health services is significantly limited by a shortage of these services, especially in rural areas, where pediatrician consultation may the only medical resource available to GP/FPs for child mental health problems. Access to psychologists' services is also limited because these are not covered by Medicare, and not all residents carry insurance for these services. GP/FPs are only remunerated for a limited number of appointments per patient for counselling, which may affect their interest in ongoing treatment.Mail out survey of GP/FPs practicing in British Columbia, Canada.In order to obtain a final respondent sample of 10% of eligible GP/FPs in the province, we randomly selected 801 names from a total of 3,953 in a registry provided by the College of Physicians and Surgeons of BC after stratification by Health Region (n = 20) to ensure a representative geographic sample. To participate in this study, physicians had to be in active general or family practice, and to see at least five children per month. From the College registry, we obtained each GP/FP's name, office address and phone number; medical specialty status, including certification in Family Medicine from the College of Family Physicians of Canada; date of birth; date of graduation, and university of graduation. Ethical approval for this study was obtained from the University of British Columbia Behavioral Research Ethics Board.The authors developed a 22-item survey questionnaire, through consultation and consensus, to cover five areas. In relation to children with four clinical conditions, namely behavior problems, social-emotional difficulties, ADHD, and mood disorders, we enquired about (1) number of patients presenting in a typical month; (2) the GP/FP's preferred approach to involvement; and (3) his/her comfort/skill and effectiveness in dealing with each condition. In addition, we assessed (4) general beliefs about children with psychosocial problems; and obtained (5) information about demographic and practice characteristics. Because our expressed aim in this survey was "to learn about how primary care physicians in BC experience providing care to children and youth with behavioral and emotional problems", we did not enquire as to details of the physicians' diagnostic or treatment methods.Behavior problems were defined as including "disruptive, non-compliant, aggressive, antisocial, oppositional and overactive behaviors"; and social-emotional difficulties as including "low self-esteem, social withdrawal and fearfulness"; and mood disorders as including "anxiety and depression". Our intention in using these terms was to allow the kind of latitude and subjectivity that physicians are accustomed to in their use of these terms in daily practice. We note, however, that the examples given in the Questionnaire to operationalize these terms, would point respondents to think of 'behavior problems' as suggestive of a possible disturbance in the range of disruptive, oppositional and antisocial disorders; and of 'social-emotional difficulties' as possibly suggestive of anxiety or depression. A draft version of the questionnaire was pilot tested with eight GP/FPs who commented on the measure's ease of use, clarity, completeness and relevance. These comments were incorporated into the final version.Preferred approach to case involvement was ascertained by enquiring about the GP/FP's usual pattern of practice regarding children with each clinical condition. Options ranged from "evaluate and manage the problem yourself" to "refer out for evaluation and management", with intermediate arrangements for combining care with specialists.Self-reported levels of comfort, skill and effectivenessGP/FPs were asked to rate their confidence and skill across four domains of clinical activity  for each clinical condition. Ratings were made on 7-point scales for each item, anchored by Very Uncomfortable/Unskilled/Ineffective (score of 1) and Very Comfortable/Skilled/Effective (score of 7).Beliefs about mental health problems in children were measured by GP/FPs' degree of agreement with four statements relating to the nature, etiology, evaluation and management of such problems (two of them adapted from the Management of Childhood Depression in Primary Care questionnaire [ionnaire ), also uPhysician personal, demographic and practice characteristics included gender; practice type ; practice location ; hours per week spent in patient care; and participation in continuing medical education activities (CME) covering children with behavioral and emotional problems over the past 5 years; as well as the number of children per month presenting with each condition type, or in whom the GP/FP would consider one of these diagnoses.Survey packages, including questionnaire, covering letter, prepaid return envelope, and a personalized $15 cheque , were mailed out in waves of approximately 200 each between November 2001 and March 2002. The initial mailout was followed 2 weeks later by a thank you/reminder letter, and 6 weeks later by a duplicate survey package to non-respondents. Two weeks later, we phoned the offices of non-responding GP/FPs to encourage participation, elucidate reasons for non-participation, and to try to confirm the GP/FP's eligibility status.In an initial data reduction step, the four comfort/skill and effectiveness items for each condition were subjected to principal components analyses (PCA). These analyses resulted in one component solutions for each condition type that accounted for a large percentage of the total variation in item scores, ranging from 76% to 83%. Each component reflected "dealing with" a particular condition type. For example, the four items concerning comfort and skill in assessing/diagnosing and managing, and effectiveness and skill in managing behavior problems, loaded uniformly highly onto a derived component for "Comfort/skill in dealing with behavior problems". Component scores were therefore created by averaging the four items for each condition type, yielding four scores: Comfort/Skill with behavior problems, social-emotional difficulties, ADHD, and mood disorders, respectively.To compare Comfort/Skill scores across condition types, we used repeated measures ANOVAs. In all analyses, we adopted a more stringent alpha level of 0.01 to indicate statistical significance (to protect against Type I error rate inflation) and an effect size of 0.5 (Cohen's d) to indicate clinical significance. To discern trends in GP/FP comfort and skill across condition types more clearly, we also characterized respondents' reported scores of 1, 2 or 3 on the relevant items as having "Low" self-reported Comfort/Skill, and those reporting scores of 5, 6 or 7 as having "High" self-reported Comfort/Skill.Multiple linear regression analyses were used to explore factors associated with Comfort/Skill scores (dependent variable) for each of the condition types. Independent variables included GP/FP background and demographic characteristics; practice characteristics; preferred approach to case involvement; and beliefs regarding care of children with behavioral/ psychosocial concerns.To explore variables associated with GP/FPs' preferred approach to case involvement, we performed a series of logistic regression analyses using the two most clearly differentiated forms of involvement for each condition type (primarily manage by yourself vs. primarily refer out). The same independent variables were used as listed above, with the addition of respondents' Comfort/Skill scores for each condition type.2 (1) = 4.2; P < 0.05); certified as specialists in Family Medicine  = 9.9; P < 0.005); and in group, as compared to solo, practice  = 9.3; P < 0.005).Of 801 questionnaires mailed, 567 were returned, and 427 completed. A total of 172 recipients were identified as ineligible to participate, including 150 who did not complete questionnaires and 22 who completed the survey form in error, as they reported seeing no children with any of the study conditions in a typical month. The remaining 405 questionnaires formed the study database, a response rate of 64.4% of eligible recipients. Table Between 75 and 80% of respondents reported seeing 1 to 4 children newly presenting with behavior problems or social-emotional difficulties, or in whom they would consider or make the diagnosis of ADHD or mood disorders, each month. Between 11% and 14% reported seeing 5 to 9 such cases for all conditions except ADHD, for which the proportion was 4.5%. Conversely, 20% of GP/FPs reported seeing no children in whom they would consider or diagnose ADHD, as compared with other condition types, for which the proportion varied from 6.2% to 6.9%.2 (1) = 9.0; P < 0.005; and χ2 (1) = 103.9; P < 0.001, respectively), whereas no differences in case involvement were found for children with social-emotional difficulties or mood disorders.Respondents frequently reported combining personal involvement with referral. GP/FPs most commonly commence evaluation and management themselves, and then refer the patient for consultation Table . We contComfort/Skill scores by clinical condition type clustered closely around the midpoint of the 1 to 7 scale: behavior problems (mean ± s.d) 3.6 ± 1.1; social-emotional difficulties 3.8 ± 1.1; ADHD 3.9 ± 1.3; and mood disorders 4.4 ± 1.3. There was a statistically and clinically significant difference between Comfort/Skill with behavior problems and mood disorders , with respondents more positive about their ability to deal with mood disorders than behavior problems. This finding is supported and extended by the data on the frequency of physicians reporting "Low" vs. "High" Comfort/Skill  ratings of 2.2 (± 1.2) and 2.4 (± 1.2), respectively. Conversely, there was a tendency to agree with the following statements: "These problems/conditions are usually related to stresses in the family which are hard to manage" and "Diagnosis/evaluation of these problems is often subjective and difficult", with ratings of 4.9 (± 1.3) and 4.4 (± 1.5), respectively  in GP/FPs' likelihood of referring out (rather than handling by him/herself) explained by Comfort/Skill was 61% for behavior problems, 53% for social-emotional difficulties, 34% for ADHD, and 60% for mood disorders.In our logistic regression analyses, only Comfort/Skill was related to preference for case involvement. Higher ratings of Comfort/Skill were strongly associated with lower likelihood of GP/FPs referring these cases out, with odds ratios  as follows: for behavior problems, 0.16 ; social-emotional difficulties, 0.21 ; ADHD 0.26 ; and mood disorders, 0.21 . Higher Comfort/Skill was therefore predictive of a tendency for GP/FPs to deal with these cases themselves. The proportion of variance  to deal with aberrant behavior, may enable GP/FPs to feel more confident with these problems. ADHD, on the other hand, continues to be a source of concern for many GP/FPs, in spite of accepted diagnostic criteria, evidence-based practice guidelines, and effective treatments. PreviousThe higher reported level of involvement and comfort/skill in dealing with mood disorders may reflect primarily work with adolescents, in which GP/FPs utilize strategies that are successful with adult patients, and drawing on the fairly extensive exposure to psychosocial medicine in family practice training. We cannStrengths of our study include its careful sampling base of GP/FPs from across the province of BC, and its breadth and depth of scope. This is one of very few studies to examine how GP/FPs as a group, deal with children presenting with a range of behavioral and emotional problems, while at the same time exploring factors that underlie some of the physicians' practice patterns, preferences and perceptions. Certain limitations of this work also need to be acknowledged. Cross-sectional studies are limited in their ability to arrive at conclusions about causality. Hence we cannot be sure, for example, that attending CME increases comfort and skill levels. It is possible that physicians who attend CME on certain topics may be particularly interested and motivated in those areas. Nevertheless, our study highlights important associations, a number of which fit with causal expectations suggested by other studies and theory. We also cannot be sure that the views of our respondents reflect all GP/FPs' perceptions and practices, given our 64% response rate, although this was considerably higher than the 54% reported for physician postal surveys overall . FinallyIt is encouraging to find that, in general, GP/FPs in BC report at least an intermediate level of comfort and skill in assessment and management. For the majority of patients, care involves the GP/FP and referral for specialist consultation. Given that specialists with skill and experience in dealing with psychosocial and mental health concerns are often in short supply, however, it would be desirable to enable GP/FPs to deal with more of these cases independently but confidently. To do so may require new educational strategies aimed at enhancing self-efficacy and capable of affecting attitudes and beliefs regarding mental health problems in children. In addition to these strategies, however, foundational changes in the way medical and support services are organized for care of children with psychosocial and mental health problems will also be required, given the barriers and challenges posed by financial and cultural factors, lack of access to specialized mental health services, and time and resource constraints within primary care ,10,29.The author(s) declare that they have no competing interests.AM, CJ, AK and SF jointly conceived the study. AM, CJ, AK, SF and MP contributed to the study design. AM was responsible for overseeing day to day coordination of the study, anddrafted the manuscript. MP performed the statistical analysis. All authors contributed to interpreting the results, and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Attention-deficit hyperactivity disorder (ADHD) is a common disorder that is associated with broad functional impairment among both children and adults. The purpose of this paper is to review and summarize available literature on the economic costs of ADHD, as well as potential economic benefits of treating this condition. A literature search was performed using MEDLINE to identify all published articles on the economic implications of ADHD, and authors were contacted to locate conference abstracts and articles in press that were not yet indexed. In total, 22 relevant items were located including published original studies, economic review articles, conference presentations, and reports available on the Internet. All costs were updated and presented in terms of year 2004 US dollars. A growing body of literature, primarily published in the United States, has demonstrated that ADHD places a substantial economic burden on patients, families, and third-party payers. Results of the medical cost studies consistently indicated that children with ADHD had higher annual medical costs than either matched controls  or non-matched controls  without ADHD. Two studies of adult samples found similar results, with significantly higher annual medical costs among adults with ADHD  than among matched controls . A limited number of studies have examined other economic implications of ADHD including costs to families; costs of criminality among individuals with ADHD; costs related to common psychiatric and medical comorbidities of ADHD; indirect costs associated with work loss among adults with ADHD; and costs of accidents among individuals with ADHD. Treatment cost-effectiveness studies have primarily focused on methylphenidate, which is a cost-effective treatment option with cost-effectiveness ratios ranging from $15,509 to $27,766 per quality-adjusted life year (QALY) gained. As new treatments are introduced it will be important to evaluate their cost-effectiveness to provide an indication of their potential value to clinicians, patients, families, and third-party payers. Attention-deficit hyperactivity disorder (ADHD) is characterized by a persistent and developmentally inappropriate pattern of inattention, hyperactivity, and/or impulsivity . ChildreADHD is associated with impairment in many areas of children's lives, including academic performance, social functioning, and overall quality of life -12. ChilBecause of the broad impact of ADHD, the disorder is likely to have serious economic implications for children, families, and society. Research has only recently begun to examine these economic costs, but the initial studies suggest that ADHD leads to increased costs in healthcare and other domains. The purpose of this paper is to review and summarize available literature on the economic costs of ADHD, as well as potential economic benefits of treating this condition. In addition, recommendations for additional research on the economic implications of ADHD are provided.A literature search was performed using MEDLINE, accessed through PubMed, to identify all published articles on the economic implications of ADHD. Searches were conducted using both the term and medical subject heading "ADHD" , along with economic terms including "cost," "costs," "economic," and "economics." Reference sections of relevant articles, including one review article that summarized eight economic studies , were reFormal cost of illness studies measure the "economic" burden resulting from disease and illness across a defined population , including both direct medical costs and indirect  costs . AlthougA majority of the medical cost studies used insurance claims data from private insurers -22,28,30The results of the medical cost studies were consistent in indicating that children with ADHD had higher annual medical costs than either matched controls  or non-matched controls  without ADHD  and adult (21% versus 1%) arrest rates compared to normal control subjects . A similOne study has estimated the economic impact of criminality associated with ADHD . Data weChildren with ADHD tend to have elevated rates of other psychiatric conditions ,49,50 FoOne study has estimated the incremental increase in costs of treatment for ADHD with comorbid conditions, compared with treatment of ADHD alone . AnalyseIn the North Dakota sample, the only comorbid conditions that were associated with lower costs compared to children without comorbid conditions were learning disabilities (-$759) and epilepsy (-$777). However, another recent study focusing on comorbid epilepsy in an administrative claims database from 1998 to 2001 found contrasting results . In a saChildren with ADHD have been shown to be more accident prone than other children , likely ADHD is associated with work-related problems in adulthood such as poor job performance, lower occupational status, less job stability, and increased absence days in comparison to adults without ADHD ,34,35,56Three published studies have utilized decision analytic modeling techniques to assess the cost-effectiveness of drug therapy (i.e. methylphenidate [MPH]) for ADHD -59 see . Each ofOverall, results of the three modeling analyses indicate that MPH is a cost-effective treatment option for children with ADHD. The cost per QALY gained in the Gilmore and Milne  study raA growing body of literature has demonstrated that ADHD places a substantial economic burden on patients, families, and third-party payers. However, all available published studies on the economic implications of ADHD are relatively recent, and there are many additional questions to be examined in future research. Thus far, studies have identified several aspects of ADHD that are likely to have economic implications, including direct treatment costs, increased rates of comorbid psychiatric disorders, high accident rates, work loss, and criminality. There are many other well-documented outcomes of ADHD that are likely to have economic implications. For example, ADHD frequently has detrimental effects on a child's academic performance and behavior in school. These difficulties are likely to place an economic burden on school systems, as there is an increased need for school-based services such as in-school medication administration; special education services; child and possibly parent counseling; educational testing; development of individualized educational programs; and efforts to address disruptive classroom behaviors ,66. ReseThe international literature on cost of ADHD could also be expanded. Nearly all published studies identified for the current review were conducted in the US. Given international differences in medical care systems and practice patterns, it is difficult to apply the direct treatment costs from US studies to countries outside the US. It is likely, however, that the indirect cost burden of ADHD identified in US studies may be similar to the burden in other countries, although it may not be recognized to the same extent. Recognition, diagnosis, and treatment of ADHD are increasing in Europe and Australia, and future studies may document the economic burden of ADHD in these areas.Finally, more work is needed on determining the potential cost-effectiveness of the various treatment options for ADHD. The initial research on cost-effectiveness of treatment has focused on MPH, and results generally indicate that treatment of ADHD is cost-effective. As new treatments are introduced , it is important to evaluate their cost-effectiveness to provide an indication of their potential value to clinicians, patients, families, and third-party payers. Effective treatments, while possibly increasing direct medical costs, are likely to reduce the overall burden of ADHD by controlling symptoms, improving children's functioning, and substantially reducing indirect costs to families.Attention-deficit hyperactivity disorder (ADHD)extended release (ER)immediate release (IR)methylphenidate (MPH)quality-adjusted life year (QALY)All three authors of this article are employed at the MEDTAP Institute at UBC, which is an independent health services research organization. Funding for the current review was provided by Eli Lilly & Co.LM was the principal investigator. He conducted the literature search, designed the structure of the manuscript, reviewed and integrated much of the literature, and wrote and conceived most of the manuscript. CP and MP had primary responsibility for the two sections that review, integrate, and summarize studies of direct costs and treatment cost-effectiveness. They reviewed the relevant literature, wrote these two important sections of the paper, and created Tables


Nonassociative learning is a basic neuroadaptive behavior exhibited across animal phyla and sensory modalities but its role in brain intelligence is unclear. Current literature on habituation and sensitization, the classic "dual process" of nonassociative learning, gives highly incongruous accounts between varying experimental paradigms. Here we propose a general theory of nonassociative learning featuring four base modes: habituation/primary sensitization in primary stimulus-response pathways, and desensitization/secondary sensitization in secondary stimulus-response pathways. Primary and secondary modes of nonassociative learning are distinguished by corresponding activity-dependent recall, or nonassociative gating, of neurotransmission memory. From the perspective of brain computation, nonassociative learning is a form of integral-differential calculus whereas nonassociative gating is a form of Boolean logic operator – both dynamically transforming the stimulus-response relationship. From the perspective of sensory integration, nonassociative gating provides temporal filtering whereas nonassociative learning affords low-pass, high-pass or band-pass/band-stop frequency filtering – effectively creating an intelligent sensory firewall that screens all stimuli for attention and resultant internal model adaptation and reaction. This unified framework ties together many salient characteristics of nonassociative learning and nonassociative gating and suggests a common kernel that correlates with a wide variety of sensorimotor integration behaviors such as central resetting and self-organization of sensory inputs, fail-safe sensorimotor compensation, integral-differential and gated modulation of sensorimotor feedbacks, alarm reaction, novelty detection and selective attention, as well as a variety of mental and neurological disorders such as sensorimotor instability, attention deficit hyperactivity, sensory defensiveness, autism, nonassociative fear and anxiety, schizophrenia, addiction and craving, pain sensitization and phantom sensations, etc. Brain calculus – or integral-differential neural dynamics – is an emerging paradigm in computational neuroscience ,2. In beprimary and secondary sensitization in analogy to pain sensitization. In Section 3, we introduce the notion of response desensitization .,64.59,64In some instances, pain sensations  may habituate upon repeated presentation of the stimuli . The paiOur definitions of primary and secondary sensitization clarify the ambiguities of the dual-process theory. The original theory pertaining to an acute spinal cat preparation was predicated on a sensitization-habituation complex observed in the cat's hindlimb flexion reflex response to a repetitive electrical stimulus. The sensitization was attributed to certain interneurons presumably located in an extrinsic "state" system that was directly activated by the primary stimulus ,11. As sprimary sensitization and habituation. Rather than mediated by an extrinsic state system as originally proposed, sensitization induced by a repetitive primary stimulus could be expressed in the primary pathway(s) as with habituation, thus evidencing primary sensitization. Indeed, as demonstrated in the frog spinal reflex, primary sensitization and habituation could occur even across the same synaptic junction ea(t-T) -for t >T     (3a)Biphasic: y = 0 for t >T     (3b)Monophasic: y(0), y(T) are respectively the outputs at the beginning and end of the step input.where From linear systems theory , the equs is the complex frequency and Y, U are the Laplace transforms of y, u, respectively.where u1 applied to the primary pathway is given by:From Eq. 2 the response of a primary integrator or differentiator Fig.  to a stet >T).where the subscript '1' indicates attribute to the primary pathway. Because of the input-gating effect (Sect. 4.4.1) the primary pathway is silenced once the primary input is off (for A secondary integrator or differentiator is described by the following model equation:2 = -a2x2 + b2u2 + b3u1y2 = c2x2 + d2u2     (6)b3 represents the influence of the primary stimulus on the secondary pathway. This model represents an integrator or differentiator if b2 and b3 have the same or opposite signs, respectively. Assuming a tonic bias input u2 in the secondary pathway and a step input u1 in the primary pathway, the response of the above secondary integrator or differentiator is:where the subscript '2' indicates attribute to the secondary pathway and and y1 and y2:Finally, the resultant response of the dual-process integrator and/or differentiator is the sum of y = y1 + y2     (8)CSP conceived the theory, reviewed and integrated the literature and wrote the manuscript. DLY performed the mathematical modeling and prepared the illustrations. Both read and approved the final manuscript.


Christine Phillips explores the roles of teachers as brokers for ADHD and its treatment, and the strategies used by the pharmaceutical industry to frame educators' responses to ADHD. Over the last twenty years, attention deficit hyperactivity disorder (ADHD) has emerged as a disorder of importance in childhood. Prescription of psychostimulants for ADHD escalated in many countries through the 1990s. Between 1990 and 1995, prescriptions of methylphenidate for young people increased 2.5-fold in the US .ADHD joins dyslexia and glue ear as disorders that are considered significant primarily because of their effects on educational performance. Medicalising educational performance can help children receive specialised medical and educational services; at the same time it can lead to them receiving medications or surgical therapies which may have short-term and long-term ill effects.In the case of ADHD, there has been a complex, often heated debate in the public domain about the verity of the illness and the personal cost-benefit ratio of treatment with psychostimulant medication . Much ofIn his essay on medicalisation processes, Conrad argued that when disorders previously viewed as non-medical are redefined as sicknesses, non-medical people often perform the “everyday routine work” of disseminating understanding of the new sickness . A tempeThe role of the teacher as the sickness and treatment broker for ADHD has been elaborated more clearly for ADHD than for any other childhood disorder. The DSM-IV diagnostic criteria accord teachers a formal role in diagnosis through specialised assessment instruments such as the Conners Teacher's Rating Scale . TeacherAn informal role also exists for teachers as “disease-spotters.” There appears to be considerable difference internationally in the alacrity with which teachers engage in disease-spotting. In a study of 491 physicians in Washington, D. C., almost half of the diagnoses of ADHD in their patients had been suggested first by teachers .As teachers have some agency in diagnosing ADHD, and may in fact contest the diagnosis, the pharmaceutical industry has an interest in directing teachers toward medical treatment. Pharmaceutical companies have been able to exploit the Internet to access teachers and to influence their brokerage role. The approach to teachers tends to mirror strategies used to familiarise doctors with pharmaceuticals.The drug promotion that masquerades as professional education is such a fixture in the medical domain that many universities train medical students to critique promotional material. Both Shire (manufacturer of Adderell)  and Nova“Make it clear to them that it is important for them—and their child—to understand and follow the doctor's medical advice about medication and other therapies for ADHD. ADHD is a serious condition that may require the child to be on medication and undergo counselling for a long duration .”Each site incorporates links to the manufacturer responsible for the site  or direcOther school personnel are also targeted. In 1997, Novartis collaborated with the National Association of School Nurses in the US to run a nationwide campaign, in which 11,000 school nurses were provided with a resource kit containing information on ADHD, its treatment, and various support organisations . NovartiIn the US, the pre-eminent advocacy group for people with ADHD is CHADD (Children and Adults with Attention Deficit/Hyperactivity Disorder). In the 2004–2005 financial year (year ended 30 June 2005), 22% of CHADD's total revenue came from the pharmaceutical industry . CHADD uA more general staking of claim to a role in schools is provided through the range of online science educational materials now provided by GlaxoSmithKline , Pfizer The organised penetration of the pharmaceutical industry associated with ADHD into the education domain is a new phenomenon. While there has been extensive discussion about the ethics of fast-food marketing within schools ,25, theIt could be argued that in providing information to teachers, pharmaceutical industries are simply acting as good corporate citizens. Such an argument would carry more weight if these companies also provided education programs addressing autism and dyslexia, two other conditions which impact upon educational performance, but which do not have accepted pharmaceutical therapies. While there is an argument for providing unbiased education to teachers about a high-profile condition, education provided by pharmaceutical companies is self-serving in that it often provides education which references their own products, and channels the reader toward medical therapy.There are calls for doctors to learn about pharmaceutical marketing strategies in their training ,27, to Teachers should be trained to decode and question marketing strategies used by the pharmaceutical industry, just as medical students are.Teachers should have a mechanism to report their observations about medication to an independent body, such as Australia's Adverse Drugs Reaction Advisory Committee.Teachers should contribute to documenting educational and other outcomes of children with ADHD, through participating in formal collation of data across school regions about outcomes.


Attention Deficit Hyperactivity Disorder (ADHD) is a genetically influenced condition although indicators of environmental risk including maternal smoking during pregnancy, low birth weight and low social class have also been found to be associated with the disorder.ADHD is a phenotypically heterogeneous disorder in terms of the predominant symptom types , their severity and comorbidity, notably Conduct Disorder. It is possible that these different clinical manifestations of the disorder may arise because of the differing effects of the environmental indicators of environmental risk. We set out to test this hypothesis.In a sample of 356 children diagnosed with ADHD, we sought to investigate possible effects of three indicators of environmental risk – maternal smoking during pregnancy, birth weight and social class – on comorbid Conduct Disorder, conduct disorder symptoms and inattentive and hyperactive-impulsive symptom severity.2 = 0.02, Beta = 0.11, t = 1.96, p = 0.05) and social class  whilst none of the environmental risk indicators significantly predicted number of inattentive symptoms. Conduct Disorder symptoms were positively predicted by maternal smoking in pregnancy  whilst both maternal smoking during pregnancy and social class significantly predicted a diagnosis of Conduct Disorder  and  respectively.Multiple regression analysis revealed that, after controlling for significant covariates, greater hyperactive-impulsive symptom severity was significantly associated with maternal smoking during pregnancy (rThese findings suggest that indicators of environmental risk, in this instance maternal smoking in pregnancy and environmental adversity indexed by lower social class, independently influence the clinical presentation of the ADHD phenotype. Other types of study design are needed to investigate whether these associations between indicators of environmental risk factors and ADHD clinical heterogeneity are attributable to causal risk effects and to further establish the magnitude of these effects. These findings have implications, not only for our understanding of the aetiology of ADHD, but may also be of clinical value, enabling the identification of individuals who are at higher risk of problematic behaviours in ADHD, notably conduct disorder, to enable earlier, targeted risk reduction strategies. Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder which affects between three and five percent of school aged children . CharactAlthough there is a large genetic contribution to the aetiology of ADHD, twin studies indicate that environmental factors are also important. Shared and unique environmental factors account for between 12 and 40% of the variance in twin ADHD scores  Pre, perLow birth weight and maternal smoking in pregnancy are the indicators of environmental risk that have been found to be most robustly associated with ADHD with results of pooled or meta-analyses showing significant evidence of association ,8.Numerous studies have reported increased rates of ADHD diagnosis and symptoms in case control studies of low or very low birth weight children -11. McCoOver the past 20 years, population based epidemiological studies -15 and cBeyond early  development, ADHD has also been shown to be associated with poverty, lower family income and social class. Epidemiological studies in the UK, USA and across the world -20 have The relations between indicators of environmental risk and ADHD are complicated. These indicators of environmental risk tend to co-occur and to be related to different behavioural outcomes that have also been associated with ADHD. Mothers who smoke are more likely to be of a lower social class and to give birth to lighter babies.  SimilarlADHD is a clinically heterogeneous disorder and there is evidence to suggest that this phenotypic heterogeneity may index underlying aetiological heterogeneity. That is, it may be that different risk pathways lead to different patterns of symptoms, symptom severity, or other clinical manifestations of the disorder. One of the main observed forms of heterogeneity lies in the pattern of comorbidity. ADHD is frequently found to co-occur with a number of other disorders, most commonly Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD). Between 43 and 93% of children with ADHD are estimated to have one of these disorders.  There isClinical heterogeneity also arises because of the preponderance of different types of ADHD symptoms, that is; Hyperactive-Impulsive symptoms and Inattentive symptoms  and theiFamily and twin studies suggest that the phenotypic heterogeneity characterised by ADHD symptom subtypes and comorbid conduct disorder or conduct disorder symptoms indexes underlying aetiological heterogeneity . There i356 British Caucasian children aged between 6 and 16 years with a diagnosis of ADHD (subsequently confirmed by research diagnostic interview assessments) were referred to the study by Child and Adolescent Psychiatrists and Paediatricians in the Greater Manchester, South Wales and Avon areas of the UK. Following informed written consent from parents and assent from children, individuals underwent a full assessment procedure. Parents  were interviewed regarding their child's ADHD, ODD and CD symptoms using the Child and Adolescent Psychiatric Assessment (CAPA).  The CAPAnd Edition), [Parents also completed questionnaires on pregnancy and birth complications  includindition),  based ondition),  of familThe protocol for this study was approved by the North West Multi-centre Research Committee in the UK.The skewness and kurtosis of all measures was calculated. For variables where skewness and kurtosis exceeded acceptable limits,  data werThe mean age of the sample was nine years and two months (SD 2 years 1 month) and 90% of subjects were male. 322 subjects (87%) met diagnostic criteria for DSM-IV ADHD . 239 subjects (64%) met diagnostic criteria for ICD-10 Hyperkinetic Disorder. The remaining 41 participants (11%) met diagnostic criteria for DSM-III-R ADHD. 47% of individuals met criteria for a comorbid diagnosis of ODD (n = 167), whilst 13% had a comorbid diagnosis of CD (n = 46). The mean number of DSM-IV ADHD symptoms was 14.74 (SD 2.45). For inattentive symptoms the mean number was 6.99 (SD 1.70) (range 0 to 9) while it was 7.74 (SD 1.49) (range 2 to 9) for hyperactive-impulsive symptoms. Mean numbers of ODD symptoms and CD symptoms were 3.86 (SD 2.49) (range 0 to 8) and 0.91 (SD 1.42) (range 0 to 8), respectively.The mean birth weight  was 3286 g with a standard deviation of 621.23 g. This is similar to the UK average birth weight (for singletons) of 3300 g . 163 mot2 < 0.001, Beta = 0.05, t = 0.85, p = 0.40).Analysis revealed significant associations between total number of hyperactive-impulsive symptoms with maternal smoking during pregnancy and social class, even when covariates including CD symptoms, age and verbal IQ were taken into account (see Table To ensure that our findings were not being driven by our modest (n = 19) number of individuals with DSM-IV ADHD Inattentive subtype, we repeated the analysis with only those meeting diagnostic criteria for DSM-IV ADHD Combined type. This did not alter our findings.Interestingly, none of the environmental measures analysed were significantly associated with total number of inattention symptoms , whilst the association with maternal smoking during pregnancy remained significant (see table 2 = 0.35 between symptoms of the disorders in this sample). Therefore caution is recommended against considering the results for these disorders as wholly independent.Maternal smoking during pregnancy significantly predicted total number of ODD symptoms . Similarly, for Conduct Disorder symptoms, maternal smoking during pregnancy was the most important factor , followed by gender .In order to ascertain which of our findings were most important, stepwise linear regression analysis was performed looking at hyperactive-impulsive and Conduct Disorder symptoms. For hyperactive-impulsive symptoms, maternal smoking during pregnancy was the most significant variable . In contrast there was a lack of association observed between any of the indicators of environmental risk and inattentive symptom severity. This finding is in line with previous twin studies which indicate a greater influence of common environmental factors  for hyperactive-impulsive symptoms, in comparison to inattentive symptoms [These findings suggest that indicators of environmental risk thought to influence the diagnosis of ADHD may also have independent effects on the phenotype manifestation of ADHD within a clinical sample, something which has not been explored in previous research. Severity of hyperactive-impulsive symptoms was independently predicted by both lower social class and maternal smoking during pregnancy, with maternal smoking during pregnancy being revealed as the most important factor. Indeed, when we further analysed the data to look at quantity of cigarettes smoked, we found a dose-dependent effect, whereby the children of mothers who reported smoking more than 10 cigarettes a day during their pregnancy had more hyperactive-impulsive symptoms than those whose mothers smoked fewer than 10 cigarettes a day  of the sample met diagnostic criteria for ODD.2 = 0.04, Beta = 0.18, t = 3.34, p = 0.001), even when other significant covariates were considered. Similarly, a diagnosis of Conduct Disorder was independently associated with maternal smoking during pregnancy. Conduct disorder (but not symptoms scores) was also found to be associated with social class. These results indicate that there is an increase in the risk of a comorbid diagnosis of CD for those ADHD children whose mothers smoke during pregnancy with an odds ratio of 3.14. Furthermore, those ADHD children from a low social class family whose mothers smoke during pregnancy are at an even greater risk of being diagnosed with Conduct Disorder (more than a five-fold increase in risk). Considering the additional impairment and risks in later life for those individuals with both ADHD and Conduct Disorder, these are potentially important findings. Environmental indicators of risk which can be easily assessed, even if not causal, can help pick up children at higher risk of adverse outcomes so that risk reduction strategies and higher levels of follow up and service involvement are targeted at those most at risk.An independent, significant association was also found between maternal smoking during pregnancy and Conduct Disorder symptoms . However, we specifically chose indicators of environmental risk which have previously been associated with ADHD and the purpose of this study was to investigate phenotypic variation within a clinical ADHD sample.Second, it is possible that, rather than showing an association between environmental factors and comorbid CD symptoms, the results of our analysis simply revealed main effects of these factors on antisocial behaviour in general. This is certainly plausible as associations between maternal smoking during pregnancy, birth weight, social class and antisocial behaviour have previously been reported. ,46 UnforThird, the failure to detect significant associations between phenotypic and indicators of environmental risk may be due to the reduced variance in ADHD symptoms in this clinical sample. However, we were interested in how the environmental factors have additional effects within the ADHD phenotype. It may even be argued that any independently significant findings are even more interesting as the power to detect them is small, although we recognise that small sample sizes can also lead to false positive findings .Fourth, our indicators of environmental risk were collected retrospectively from self report. It is possible that these measures are inaccurate. Furthermore, our question assessed maternal smoking during pregnancy generally, rather than separating it into different trimesters. We therefore cannot determine whether or not there are differing effects of maternal smoking during pregnancy between those who give up at some point during the pregnancy. However, retrospective self report of maternal smoking during pregnancy has been shown to be relatively accurate, corresponding with both contemporary reports  and blooFifth, social class is unlikely to be a proximal risk factor and is certainly only an indicator of risk. However, it is an easily obtainable indicator of risk that is readily available in clinical practice. Given these findings, there is clear justification for measuring and examining potential proximal risk factors that are indexed by social class and that may have effects on the clinical presentation of ADHD.Sixth, as discussed previously, these indicators of environmental risk (and indeed the phenotypic measures) show covariation. It is therefore possible that our findings are the result of a separate, unmeasured factor, associated with both the environmental and phenotypic measures. In this analysis, we control for a number of possible covariates by including every environmental indicator measure in the multivariate analysis, whilst also controlling for a range of demographic and clinical variables found to be associated with the phenotypic variable.The environmental indicator measures chosen represent easily obtainable indicators of risk, but are not necessarily causal themselves. Other designs are needed to test whether the associations are due to causal risk effects . NeverthFinally, there may be a genetic link between our indicators of environmental risk and our phenotypic measures. For example, maternal smoking during pregnancy and child ADHD or conduct disorder behaviour; antisocial or ADHD mothers may be more likely to smoke during pregnancy  and In summary, in a clinical sample of children with ADHD, we have observed that maternal smoking during pregnancy and social class independently predict severity of hyperactive-impulsive symptoms and Conduct Disorder symptoms and diagnosis. Conversely, the indicators of environmental risk studied did not predict total number of inattentive symptoms. Previous research has focused on main effects of maternal smoking during pregnancy, birth weight and social class on diagnosis of ADHD. The findings of this study now suggest that that some of these indicators of environmental risk may also have an effect on the clinical manifestation of the disorder.AT has accepted fees from pharmaceutical companies including Janssen Cilag and Eli Lily for talks and meetings. The other authors  declare that they have no competing interests.KL was responsible for the data collection, analysis and interpretation of findings. She also drafted the manuscript. PH provided statistical expertise and was involved in the interpretation of findings. He also edited the manuscript. MBMvdB was involved in the design, data collection and interpretation of the study. She also edited the manuscript. AT was responsible for the design and coordination of the study, was involved with interpretation of the findings and revised the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie?We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered.The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment. ADHD is one of the most well-recognized childhood developmental problems. This condition is characterized by inattention, hyperactivity and impulsiveness. It is now known that these symptoms continue as problems into adulthood for 60% of children with ADHD. That translates into 4% of the US adult population, or 8 million adults. However, few ADHD adults are identified or treated. Adults with ADHD may have difficulty following directions, remembering information, concentrating, organizing tasks or completing work within time limits. If these difficulties are not managed appropriately, they can cause associated behavioral, emotional, social, vocational and academic problems. ADHD afflicts 3% to 7.5% of school-age children -4. An esThe diagnosis of ADHD is based on criteria outlined by the Diagnostic and Statistical Manual of the American Psychiatric Association Version 4-TR . This isEstimates of the frequency of the various types of ADHD, based on population surveys, have shown variable results. The advantage of population based samples, in contrast to clinic based samples, is that individuals in the community who have not sought medical attention are included. Table It is one thing to read a list of the symptoms in Table Individuals with ADHD have a very low level of tolerance to frustration and stress. This results in irritability and poor anger control. The anger tends to come on suddenly and explosively with slamming doors, punching holes in walls, verbal abuse of those around them, tantrums, and leaving important meetings in a frenzy. Children get into fights, adults blow up and lose jobs and alienate friends. Afterwards they are sorry, but the damage is done. Because of their low tolerance for frustration they are very impatient. They hate to wait in line, and delays of any kind make them frantic. Whatever is going on – a trip, a movie, a class, a discussion – they want it to go quickly and be finished. Because of their impulsivity both children and adults may leap into action without thinking of consequences. As adults, they drive too fast, use power tools carelessly, and plunge into activities without thinking of the danger. As children they often appear fearless, do dangerous things, climb too high in trees, and may dart into traffic without looking. The result is they often hurt themselves or others. People with ADHD have trouble with their orientation to time and space. They may have to stop and think which is their right hand and which is their left; may have difficulty following a set of instructions, reading a map or telling time. People often complain they can never get to places on time. Because of their difficulty in planning ahead, they leave too little time to get places. If they live 30 minutes from the place of an appointment, they often leave home at the time of the appointment, making themselves 30 minutes late. It takes little imagination to realize that may of these traits make for difficult interpersonal relationships and problems in school and on the job. With adults a history of many failed marriages and many job changes is common. This is a flavor of just some of the issues that ADHD children and adults face.For many years, clinicians caring for children with ADHD have noted that the condition is common in one or both of the parents. While this suggests that ADHD may have a strong genetic basis, environmental factors could cause the same familiar pattern. Twin studies provide much stronger evidence for the role of genetic factors. Several large twin studies of ADHD have been completed in the last 15 years. They show that the concordance rate in identical twins is usually greater than 65% while that in fraternal twins is usually less than 40%. This is consistent with 75 to 95% of ADHD being genetically caused, the remainder being environmental . One reaThe environmental portion can be divided into a shared and unshared component. The shared component refers to exposure to the same environment while the unshared portion refers to exposure to different environments. The former is more likely to occur early in childhood, while the latter is more likely to occur later in childhood. The early shared environment is the part of life that Freud and many other psychiatrists and psychologists assumed was the most formative part of a child's life in terms of their adult behavior. An additional part of the twin studies of great interest was that the shared environment was usually found to contribute to essentially 0% of the environmental component . Most ofA number of adoption studies of ADHD have also been reported -11. ThesWhen diseases or disorders or traits are due to genetic factors, there are several mechanisms by which they can inherited. Such conditions can essentially be divided into single gene disorders and polygenic disorders. Single gene disorders include hemophilia, cystic fibrosis, neurofibromatosis and Huntington disease. In single gene disorders a rare mutation results in the complete disruption of the function of a gene. Some of the greatest advances in genetics during the past 100 years have come from the elucidation of the genes for virtually every single gene disorder. Their DNA has been cloned, sequenced and the gene localized to a specific chromosomal region.Polygenic disorders, by contrast, are due to the interactive or epistatic effects of many different genes on different chromosomes, each gene contributing to only a small part of the picture (variance). These genes interact with environmental factors. Except for a few rare families , all behIn association studies of a wide range of behavioral disorders, even when the association is significant the percent of the variance attributable to that gene is usually in the 0.5 to 3% range and averages less than 1.5%. This suggests that even if genes only account for 72 to 95% of the total variance, 50 or more different genes would be involved -17. ThisIt has been known for many years that if an individual inherits enough genes to develop any given behavioral disorder, their risk of developing a second behavioral disorder is 2 to 4 times greater than for the general population. This is probably because different behavioral disorders share some gene variants. Thus, the more a person exceeds the required threshold number of gene variants, the greater the likelihood they will develop more than one behavioral problem, thus the term spectrum disorders. Some of the most common coexisting or comorbid spectrum disorders seen in individuals with ADHD are oppositional defiant disorder, conduct disorder, major depressive disorder, anxiety disorders, obsessive compulsive disorder, bipolar disorder, learning disorders, and substance abuse disorder including alcoholism and drug addiction. The frequency of some of these disorders is illustrated in Figure After viewing the DSM-IV criteria for the diagnosis of ADHD, one of the most commonly voiced objections is, "every child has some of those symptoms." As with every other polygenic trait, ADHD symptoms lie on a continuum of severity. This is true of height, weight, IQ, blood pressure, cholesterol level, depression, dyslexia, anxiety and may other characteristics. These traits follow a bell-shaped curve of magnitude or severity. Many children have too few symptoms to meet the criteria. They may be somewhat inattentive or hyperactive at times but they do not meet all the criteria of ADHD. Note that 6 or more symptoms must be present, must meet the qualifiers of severity in the diagnostic criteria  they must be present for 6 months or more and must be maladaptive and inconsistent with the normal developmental level. Because of these qualifiers some individuals may barely meet the criteria and are sufficiently mild not to require treatment. Others, however, are at the extreme end of the bell-shaped curve and are so symptomatic that everyone coming into even brief contact with them can suspect the diagnosis. Physicians arbitrarily pick a cut-off point for many diseases or disorders. Those on the extreme end of the curve have the disorder, those with less extreme symptoms do not. This may give a false illusion of a dichotomous trait. For example, the diagnosis of hypertension is usually based on a consistent diastolic blood pressure of 90 mmHg or more. Some individuals have severe life threatening hypertension with a diastolic blood pressure consistently above 120 mmHg while others have mild hypertension where the diastolic blood pressure is sometimes normal and sometimes too high. Because it is a continuum does not mean hypertension does not exist.An even better example is depression. Everyone is occasionally depressed. This does not mean the diagnosis of major depression is invalid or worthless because everyone can relate to it. Some are so depressed they sleep all the time, can't get out of bed, eat poorly, lose or gain weight, have zero libido, are suicidal and desperately need treatment. Ironically, even some professionals who clearly understand that major depression is a real entity but lies on a continuum of severity may have trouble understanding that the same is true of ADHD. The cut-off point is set to secure help for those with symptoms severe enough to interfere with their lives, and leave those with minimal symptoms with no diagnosis.One of the most common misconceptions about ADHD is that it goes away by the time an individual is a young adult. In California, this is written into the MediCal law. Stimulants are no longer covered for the treatment of ADHD in adults because it is assumed the disorder is gone by that time. One feature leading to this misconception is that motor hyperactivity often does decrease with age. However, there is much less decrease in inattention, and if individuals are rated on a global assessment of functioning, there is little improvement with age .While stimulus overload is especially characteristic of children with autism, many children with ADHD are also very sensitive to sound, sight, smell or other sensory inputs . AwareneTwo pathways relevant to learning are that linking the linguistic cortex to the hippocampus and that for remembering visual images, which links the visual cortex to the hippocampus via the dorsolateral medial entorhinal cortex . The latThere have been a number of longitudinal studies of ADHD in which a group of individuals diagnosed in childhood were followed for a number of years to assess how they performed as adults -23. In mA second disorder commonly comorbid with ADHD is oppositional defiant disorder (ODD). The DMS-IV criteria for ODD are given in Table Having pointed out that much of the poor outcome in ADHD children is due to the comorbid presence of CD, we would like to present the 1985 study by Howell and coworkers . While tMany of the symptoms of ADHD parallel the symptoms of individuals with destructive lesions of the prefrontal lobes -35. WhenIn some children with ADHD, especially those with learning disorders, the parietal lobes are also likely to be involved . Studieset al. . The reward pathways of the brain are also located in the frontal lobes and limbic system. They provide pleasure for a number of behaviors that are critical to the continued existence of the individual and the species, such as eating and having sex. These are termed natural rewards. The reward pathways are rich in dopamine carrying neurons and it is the release of dopamine that produces the feelings of pleasure. In addition to food and sex, all drugs of abuse result in the release of dopamine in the reward pathways. This is responsible for the feelings of euphoria or the high that these drugs produce. These are termed unnatural rewards. We have previously proposed a Reward Deficiency Syndrome (RDS)  suggestiet al.  found annt trait .2A1 allele compared to 25.9% of the 714 known non-Hispanic Caucasian controls screened to exclude drug and alcohol abuse; p <0.000001, odds ratio = 2.96 [DRD2 gene was associated with severity in that the D2A1 allele was present in 63.8% of those in the upper half of severity (odds ratio versus controls = 5.03) compared to 40.9% in the lower half of severity. Of those who had no comorbid substance abuse, 44.1% carried the D2A1 allele, compared to 60.5% of those who had comorbid substance abuse. These results suggest that genetic variants at the DRD2 gene play a role in pathological gambling and support the concept that variants of this gene are a risk factor for impulsive and addictive behaviors 49Different neurological studies have found pathological gamblers to have high impulsivity and poor performance in tasks involving frontal/executive functions. These symptoms are similarly observed with individuals diagnosed with ADHD. It is noteworthy that pathological gambling is an addiction that is not confounded by the problems of ingesting a drug. PET studies of individuals engaged in video poker have documented a release of dopamine in the striatum . We founo = 2.96 . The DRDIn this regard, others have utilized questionnaires, structured interviews and behavioral tasks to evaluate the history of ADHD in pathological gamblers. It was found that pathological gamblers scored higher on the Barratt Impulsivity Scale (BIS) than controls, but only those with a history of childhood ADHD showed a greater impulsivity in behavioral tasks .As discussed below, it has often been claimed that the treatment of ADHD with stimulants will encourage children to abuse drugs when they are older. It is much more likely that ADHD and substance abuse share many gene variants in common, and share a deficiency of dopamine in the frontal lobe and limbic system, and this is the reason ADHD and especially ADHD + CD children are also at risk for substance abuse. The best way to prevent substance abuse is to ensure that the ADHD and the resulting frontal and parietal lobe dysfunctions are adequately treated so these individuals do not turn to street drugs to self-medicate. Studies suggest that the prevalence of substance abuse disorder is lower in ADHD children who are adequately treated with stimulants than in those who are untreated .It is one thing to know that a disorder is largely genetic and another to know which genes are involved, especially if the disorder is polygenically inherited. Because each gene contributes to only a small part of the total picture, the gene variants involved can be difficult to identify. The most powerful method is the use of association studies. These studies compare the frequency of gene variants (polymorphisms) in individuals with and without ADHD, or examine whether certain gene variants are preferentially transmitted to a child with ADHD. The genes that have been examined in ADHD and related behavioral disorders tend to be in three classes: enzymes, receptors and transporters, especially those that involve neurotransmitters. Binding to the post-synaptic cell occurs at receptors that are specific for a given transmitter. In addition to being broken down by enzymes, the neurotransmitters can be cleared from the synapse by transporters that return the neurotransmitters to the pre-synaptic cell. As with the receptors, the transporters are neurotransmitter-specific. Perhaps the best known example is the serotonin transporter. Drugs that inhibit the action of the serotonin transporter are called selective serotonin re-uptake inhibitors or SSRIs., the dopamine transporter (DAT1 or SLC6A3), the serotonin transporter (HTT or SLC6A4), norepinephrine receptors , the norepinephrine transporter (NET or SLC6A2), and others [There are an estimated 25,000 human genes. More efficient methods for testing large numbers of genes in association studies are rapidly being developed. Until these techniques are fully developed and relatively inexpensive, we perforce examine the genes (candidate genes) that we feel are most likely to be involved. To date, variations at a number of candidate genes have shown a significant association with ADHD. These include genes for three dopamine receptors d others ,16,52. ODAT1 gene are also very hyperactive [DAT1 gene [The most frequently examined variant in the dopamine transporter is a 40 base pair repeat polymorphism. The most common variants or alleles are called 9 and 10. A number of studies have shown that the 10 allele is more common in Caucasians with ADHD. Brain imaging studies show an increased availability of the dopamine transporter in ADHD subjects compared to controls across all age groups . It is eeractive . While tAT1 gene . FurtherAT1 gene  that chiAT1 gene  also repA number of genome scans, using sibling-pair linkage techniques for identifying relevant genes, have been performed ,59. A nuDAT1 and other genes contribute to only a modest part of the total picture, a more powerful method of examining the genetics of ADHD may be to test the interactive (epistatic) effects of multiple genes. Preliminary studies simultaneously examining variants at 42 different genes indicate the importance of norepinephrine genes in the etiology of ADHD [Because the  of ADHD . These s of ADHD -65.Many double blind studies over the past 40 years have agreed that stimulants such as methylphenidate, dextro-amphetamine, and others are very effective in the treatment of 70–80 % of children and adults with ADHD. One of the myths of ADHD is that ADHD children show a paradoxical effect of being calmed by stimulants while "normal" individuals are stimulated by them. However, studies have shown that activity levels are decreased and attention levels are increased by stimulants in individuals with and without ADHD. The difference is that since the levels of hyperactivity and inattention are much higher in ADHD subjects, the improvement is relatively much greater, giving the impression that they respond while non-ADHD subjects do not.2 receptors. When the nerve is stimulated . Since hyperactivity is related to excessive dopamine activity in the basal ganglia, this would seem on the face of it to make things worse instead of better. However, Figure d Figure , the amotor tics . The stiTaq A1 allele [Despite this indication of how well-suited stimulant medications are to the treatment of ADHD, many still worry that our children are receiving a form of "speed." Studies have shown that in order to obtain a "high", stimulants need to reach the brain very quickly. This requires intravenous or nasal administration, or the use of doses that exceed therapeutic recommendations. At therapeutic oral doses the stimulants used for treatment of ADHD do not cause a euphoric high. Perhaps the best indicator of this is that one of the hardest parts of the treatment of ADHD children is to get them to take their medication; they do not come begging for more. This, however, is no guarantee that these drugs are never abused. It is important that children and adolescents with ADHD should not have free access to their medications, since it is clear that these drugs can be abused when given nasally, or intravenously or in high doses. Keeping track of the medications helps to ensure that they are not sold for illicit use. There is also the potential problem of inducing aggressive behavior in those individuals possessing the DRD2 1 allele .A second class of medications that work primarily on norepinephrine pathways, such as clonidine, guanifacine, and atomoxetine, can also be quite effective. Clonidine and guanifacine are especially useful in treating individuals with both ADHD and chronic tics (Tourette syndrome) since clonidine and guanifacine uniquely treat both these conditions . PhysiciAs indicated above, it is often the comorbid disorders such as ODD and CD that cause the greatest distress to parents of children with ADHD. In our experience, the atypical neuroleptics such as risperidone, olanzipine and molindone can be very effective in the treatment of these comorbid conditions.Because of their concern about the use of medications, many parents seek alternative methods of treatment of ADHD. Most clinicians agree that a combination of medication and behavioral modification is the most effective approach to the treatment of ADHD, even though the medications contribute the most . ChildreFamily therapy relates to therapy that involves every member of the family. This can be especially effective since there are often many issues that affect the entire family. These involve educating the parents, siblings and affected child that ADHD is a genetic-biochemical disorder and is not the child's fault. This does not mean that ADHD children should not be held responsible for their behavior. It does mean that the level of discipline needs to be modulated by an understanding of the biological basis of the disorder. Family therapy can also address the frequent concern of siblings that the misbehaving child often gets a disproportionate degree of attention. Many other issues relating to having a child with ADHD in the family benefit from family therapy and parent education.EEG biofeedback usually utilizes feedback from a game played on a TV screen to attempt by training to alter the levels of alpha, beta and delta waves in the brain. It has the advantage that no drugs are used and it appears to be effective in some cases . The disA large number of herbal remedies have been used by ADHD patients. Sometimes they seem to be effective, sometimes not, or their effectiveness may be short-lived. Many parents turn to them because they are perceived as "natural." However, to be effective they must contain an active ingredient and the identity of this ingredient is usually not known. In addition, a wide range of other ingredients may be present that are not necessary or may cause undesirable side effects .In contrast to herbal remedies, the compositions of neutriceuticals are precisely known. They usually consist of amino acids, vitamins, minerals and other known compounds. Because they are closer to food substances than drugs, they do not have such rigorous FDA restrictions as drugs and can be purchased over the counter. Because a number of amino acids have direct or indirect effects on the levels of specific neurotransmitters, they have the potential for helping to control some of the symptoms of ADHD. Neutriceuticals have the advantage that double-blind studies can be easily carried out. It is not unlikely that some combinations of the above compounds, carefully tested in double-blind studies, may play a supporting role in controlling some of the symptoms of ADHD -75.th century could have played such a role. These are the availability of effective birth control in the 1960s, and the dramatic increase in the percentage of individuals attending college since the Second World War. Individuals carrying genes for ADHD and learning disorders are less likely to go on to college and post graduate work and more likely to start a family in their early 20 s. Individuals who do not carry these genes are more likely to attend college and put off childbearing into their late 20 s or early 30 s. This would result in a more rapid increase in the first set of genes. Whether this would be sufficient to account for an increase in frequency of ADHD and autism must await studies of the frequency of a range of genes by birth cohort.The frequencies of both autism and ADHD have appeared to increase in the last decade or more. There has been particular emphasis on the possibility that the presence of mercury in vaccines might play a role in this increase. These issues have been reviewed in detail by Kirby , includiAt the 4th International meeting of the Attention Deficit Hyperactivity Disorder Molecular Genetics Network, chaired by Stephen V Farone, investigators from around the world convened in May 2002 at Harvard Medical School and presented their findings about genes and ADHD. The putative ADHD genes with pooled odds ratios greater than 1.0 included the following: DAT1 = 1.3; DRD4 = 1.4; DRD5 = 1.5; and 5HT1B = 1.5. It was concluded that although technological and statistical advances in molecular genetics have allowed researchers to begin to identify the association of specific genes with ADHD, continued collaborative efforts are needed to elucidate the genetic underpinnings of this complex phenotype fully . Since tADHD is a common, complex, polygenic genetic, but highly treatable disorder that can have a profound lifelong effect on brain function. The genes currently identified as playing a causative role in ADHD account for only a small percentage of the total picture. The identification of additional ADHD, CD and ODD genes, and their interactions, holds the promise of firmly establishing ADHD as a biological disorder and of identifying better methods of diagnosis and treatment, emphasizing the need for polypharmacy.ADHD Attention deficit hyperactivity disorderADHD-C ADHD combined typeADHD-H ADHD hyperactive typeADHD-I ADHD inattentive typeADRA2A adrenergic A2a receptor geneADRA2C adrenergic 2C receptor geneBDNF brain derived neurotrophic factorCD Conduct disorderDAT dopamine transporterDAT1 Dopamine transporter Genetic Engineering News2 receptor geneDRD2 Dopamine D4 receptor geneDRD4 Dopamine DDSM-IV-TR™ Diagnostic and Statistical Manual of the American Psychiatric Association -IV Text revisionFDA Federal Drug AdministrationEEG electroencephalogramHTT serotonin transporter geneIQ Intelligence QuotientNET norepinephrine transporter geneODD Oppositional defiant disorderPET Positron emission tomographyRDS Reward Deficiency SyndromeSLC6A3 Dopamine transporter geneSLC6A4 serotonin transporter geneSLC6A2 serotonin A2 receptor geneSNAP25 synaptosomal-associated protein, 25kDaSSRI Selective serotonin reuptake inhibitorsTaq I Taq I restriction endonucleaseTPH2 tryptophan hydroxylase 2VNTR variable number tandem repeatsThe author(s) declare that they have no competing interests.David Comings major primary authorThomas JH Chen – Co-AuthorKenneth Blum- Co-AuthorJulie Mengucci- Prime editorial reviewerSeth H. Blum- Stylistic References and reviewBrian Meshkin- Co-editorial reviewer


Diagnostic stability and illness course of chronic non-organic psychoses are complex phenomena and only few risk factors or predictors are known that can be used reliably. This study investigates the diagnostic stability during the entire course of illness in patients with non-organic psychoses and attempts to identify non-psychopathological risk factors or predictors.100 patients with functional psychosis were initially characterised using the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), medical records and health registers. To study the stability of diagnoses (i.e. shifts per time), we used registry data to define four measures of diagnostic variation that were subsequently examined in relation to four possible measures of time . Afterwards, we identified putative co-variables and predictors of the best measures of diagnostic stability.All four measures of diagnostic variation are very strongly associated with numbers-of-hospitalisations and less so with duration-of-illness, duration-of-hospitalisation and with year-of-first-admission. The four measures of diagnostic variation corrected for numbers-of-hospitalisations were therefore used to study the diagnostic stability. Conventional predictors of illness course – e.g. age-of-onset and premorbid-functioning – are not significantly associated with stability. Only somatic-comorbidity is significantly associated with two measures of stability, while family-history-of-psychiatric-illness and global-assessment-of-functioning (GAF) scale score show a trend. However, the traditional variables age-of-first-admission, civil-status, first-diagnosis-being-schizophrenia and somatic-comorbidity are able to explain two-fifth of the variation in numbers-of-hospitalisations.Diagnostic stability is closely linked with the contact between patient and the healthcare system. This could very likely be due to fluctuation of disease manifestation over time or presence of co-morbid psychiatric illness in combination with rigid diagnostic criteria that are unable to capture the multiple psychopathologies of the functional psychoses that results in differential diagnoses and therefore diagnostic instability. Not surprisingly, somatic-comorbidity was found to be a predictor of diagnostic variation thereby being a non-psychiatric confounder. Some patients with functional psychoses experience a single diagnosis and few hospital admissions while others are subject to frequently changing diagnoses and repeated hospital admissions . These dFirst, we used lifetime-structured interviews (OPCRIT), medical records and the Danish health registers to collect putative factors affecting or predicting diagnostic stability. Second, we analysed these factors in relation to comprehensive data from the Danish health registers covering all hospital admissions of the particular subjects in order to their study impact on the diagnostic stability.The study has been carried out in accordance to the Helsinki Declaration. The Danish Data Protection Agency and the Danish Scientific-Ethical Committees (file # 01-024/01) have approved the study.All patients had given written informed consent prior to inclusion into the project: Danish Psychiatric Biobank. At the time of recruitment and rating no subject was subdue to civil or forensic psychiatric restraint.A cohort of 100 subjects with functional psychoses was randomly sampled among the 359 patients participating in the genetic research project, Danish Psychiatric Biobank, by 2004. The representative character of the examined sample is documented by the duration of illness  showing that both recent onset cases are represented as well as highly chronic patients ,7. The rFurther, clinical data, including the latest principal ICD-10 diagnoses, were extracted from interviews and medical records using a standardized schema made for the purpose with focus on the patient's history. [Generation of reliability measures regarding the clinical interviews using the standardized schema has not been possible due to the logistic set up of the study.] In order to improve the overall quality of the clinical data, all schemas on the 100 samples has been thoroughly proof read by consultant KDJ.Information on all hospital contacts  as well as corresponding principal ICD-8 diagnoses 1965–1994] and ICD-10 diagnoses [1994–2006] was obtained through the Danish, Psychiatric Central Research Register [65–1994 aICD-8 (1965) was used as diagnostic criteria until 1994 as ICD-9 (1975) was newer introduced in Denmark. ICD-10 (1989) has been used from 1994 to present date as the diagnostic criteria. ICD-8 diagnoses relating to functional psychoses were translated into the corresponding ICD-10 diagnoses as shown in table Three classes of variables were used:A number of variables relating to events during illness course were obtained from the lifetime clinical & OPCRIT interviews. These variables primarily relate to the functional criteria of the St. Louis diagnostic system  as shownFour putative measures of time  to be used in the analysis of stability were defined as shown in table Four complementary measures of diagnostic variation were defined table : 1. NumbThe two latter measures of diagnostic variation were created in order to discriminate repeated shifts that occur between the same few diagnoses from shifts between many diagnoses across the entire diagnostic systems during the course of illness.® and the scripting language PHP. All analyses were preformed using SAS® 9.1 and SigmaStat® 3.1. Univariant analysis was used to examine the relation between the four measures of diagnostic stability and the four measures of time. Bi-variate regression analyses were used to estimate the individual contribution to the diagnostic variation, while correcting for numbers-of-hospitalisations. Multiple regression analysis with backward elimination was used to determine which combination of independent variables that could explain the observed variation in numbers-of-hospitalisations.All data were administrated using the database MySQLComplete data on hospitalisations and diagnoses covering the entire duration of illness was available on 89 of the initial 100 subjects, leading to the exclusion of 11 patients. Data from the registers and clinical interviews revealed that these 89 subjects were highly phenotypic representatives of a cohort of chronic patients with functional psychoses, as shown in table As preparatory step to study diagnostic stability, we first defined four different measures of diagnostic variation that describe the numbers of shifts in diagnoses and in diagnostic spectra as well as the complexity associated with these two type of shifts (for details see section on Methods). Table Stability is defined as variation over time. As the next step we therefore attempted to identify the most appropriate measure of time with which to correct the measures of diagnostic variations (defined above) and thus allow us to study diagnostic stability. Consequently, four measures of time were defined table : numbersUsing univariant analyses we found that of the four time measures, number-of-hospitalisations, was significantly better than the other three time measures associated with all the four measures of diagnostic variation table . Thus, nIn order to study diagnostic stability, we performed bi-variate regression analyses with the four measures of diagnostic variation as dependent variables and numbers-of-hospitalisations as an obligate independent variable and each of the putative predictors or risk factors listed in table We found that somatic-comorbidity was significantly correlated with the numbers of shifts in diagnoses and in spectra explaining approximately 3% of the diagnostic variation of each, but somatic-comorbidity was not associated to diagnostic-complexity or spectrum-complexity  have no significant explanatory power in relation to the four measures of diagnostic variation in this sample.Second, among the examined independent variables, somatic-comorbidity significantly added explanatory power to two of the four measures of diagnostic variation (i.e. numbers-of-diagnostic-shifts and numbers-of-spectrum-shifts) but not to those of diagnostic-complexity or spectrum-complexity. Somatic-comorbidity is also highly significantly associated with numbers-of-hospitalisations  and therefore explains the observed diagnostic variation in both an independently and dependently manner.This is most likely because somatic-comorbidity in mentally ill patients raises the question of possible organic psychiatric illness when initially identified in the healthcare system. This leads to additional differential diagnoses, further diagnostic variation and more psychiatric hospitalisations due to possible liaison-psychiatric reasons. Once diagnosed, somatic-comorbidity becomes psychiatrically neutral, i.e. it does not cause the psychiatric diagnosis to change. However, it may cause more hospitalisations due to somatic admission during psychiatric admissions.Third, the Finnish epidemiologists Isohanni and Moilanen ,13 previFourth, we find that numbers-of-hospitalisations is the best time measure to be used in relation to diagnostic stability, as it explains as much as half of the diagnostic variation. This is not surprising, as a contact with the healthcare system is necessary in order to have a diagnosis in the first place and to have following diagnostic shifts. We also find that the variation in numbers-of-hospitalisations itself can be significantly predicted by age-of-first-admission, civil-status, first-diagnoses-being-schizophrenia and somatic-comorbidity that account for up to two-fifth of the observed variation. This is anticipated, as subjects with an early onset of severe illness (e.g. schizophrenia) and somatic-comorbidity, who  are less likely to find a spouse, are more prone to experience additional contacts with the healthcare system.Fifth, the diagnostic variation over time may equally well reflect the multiple variations in the psychopathology of the illnesses or presence of comorbid mental illnesses that at different hospitalisation events generates multiple differential diagnoses due to the present inflexible diagnostic criteria. The contemporary operational and categorical diagnostic systems are unable to embrace the whole phenomenology of the schizophrenia spectrum disorders, such as e.g. coexisting psychotic and affective symptoms, as previously described by our research group . Our stuFinally, our results demonstrates the utility of the Danish psychiatric registers to longitudinal validation of the stability of clinical diagnoses of patients that participate in research studies of e.g. genetic nature.This study presents a new experimental strategy to study diagnostic stability based on comprehensive data of the pattern of hospitalisation and diagnoses during the entire course of illness of the particular subject. This strategy identifies several risk factors or predictors of diagnostic instability in subjects with chronic schizophrenia spectrum disorders. The study also shows that none of the conventional predictors e.g. age-of-onset and family-history-of-psychiatric-disease is significantly associated with the diagnostic stability observed in this sample, whereas somatic-comorbidity is related to several measures of stability in both a direct and indirect manner. The study also revealed that the nosocomial variable, numbers-of-hospitalisations is the best measure of time in relation to diagnostic stability, and that the variation in numbers-of-hospitalisations itself may be explained by the variables age-of-first-admission, civil-status, first-diagnosis-being-schizophrenia and somatic-comorbidity.The author(s) declare that they have no competing interests.KDJ: Conception and design of the study and analysis, data analyses, interpretation of results and writing of the article.TH: Design of data administration and analysis, data analyses, interpretation of results and reading, commenting and approval of the manuscript.TW: Design of study and data analysis, interpretation of results, revision and final approval of the manuscript.First and second author contributed equally to this work.The pre-publication history for this paper can be accessed here:


We read with special interest the article by We would like to focus on the potential neuroprotective role of iron against the deleterious effect of lead on the development of ADHD symptoms.Although the mechanisms underlying ADHD remain unclear, both genetic and environmental factors have been implicated. In a recent review on the implication of the dopaminergic system in the etiology of ADHD, Lead in the central nervous system may contribute to dopaminergic dysfunction inducing alteration of dopamine release and dopamine receptor density . MoreoveIn a controlled comparison group study, we  showed tGiven that lead exposure may contribute to ADHD and iron deficiency may exacerbate deleterious effects caused by lead, we recommend systematically seeking for iron deficiency in children with ADHD. We also think that controlled studies assessing the potential effectiveness of iron supplementation on ADHD symptoms should be encouraged. Such studies could aid the understanding of the complex pathophysiology underlying ADHD and provide effective therapeutic strategies for this disorder.


The objective of this study was to analyze the extracellularly acting semicarbazide-sensitive amine oxidase (SSAO) serum levels in children with ADHD for the first time. SSAO is known to show deviations from normal in various somatic disorders and to interplay with the intracellularly active MAO. In humans two forms of SSAO a circulating form in plasma and a membrane-bound form are involved in monoaminergic metabolism.We analyzed serum levels of SSAO in 27 children meeting ICD-10 criteria of Hyperkinetic Disorder (F90) or DSM-IV criteria of ADHD combined type by HPLC method and fluorimetric detection. A group of 42 healthy volunteers within the same age range (7.0 – 14.0 years) served as controls.No significant differences between children with ADHD  and healthy controls  in SSAO serum levels were found . Further, stimulant medication status had no influence on the result .There is no evidence for a deviation of SSAO serum activity in ADHD. Hence, extracellularly acting SSAO does not seem to be a promising factor for further research in ADHD. But progress in knowledge of its physiologic role and of the relationship between the membrane-bound and the circulating serum form may open new avenues for research on SSAO in ADHD. There is increasing evidence that deviations of the dopaminergic, noradrenergic, and serotonergic systems are involved in attention deficit hyperactivity disorder (ADHD) . SeveralIn children with ADHD, significantly lower levels of platelet MAO activity seem to be associated with increased impulsivity and inattention . In addiOther aminoxidases like the semicarbacide sensitive amino oxidase (SSAO) may also be involved in ADHD. Since SSAO acts extracellularly, it may work complementary to the intracellular activity of MAO . AdditioIn humans two forms of SSAO have been detected: a circulating form in plasma and a membrane-bound form. Both forms of SSAO metabolize several aromatic and aliphatic primary amines including dopamine while generating at the same time hydrogen peroxide and ammonia. The presence of SSAO in human cerebrovascular tissues and in endothelial cells from microvessels (including the blood-brain barrier) ,13  or DSM-IV criteria of ADHD combined type   served as controls.In view of the fact that SSAO circulating in plasma is quite stable  only oneThis pilot study was carried out with the approval of the local Ethics Committees of the Medical Faculties of the Universities of Erlangen-Nuremberg and Goettingen. Written informed consent has been obtained from all parents and the patients able to write; younger children gave their oral assent.The SSAO activity was determined according to a method of van Dijk et al. , modifieAfter precipitation of the proteins contained in the reaction mixture and stopping of the reaction, the benzaldehyde formed was derivatized with 5,5-dimethyl-1,3-cyclohexandione (dimedone) from the supernatant, which specifically reacts with aldehydes. The derived material was quantified using an isocratic HPLC method and fluorimetric detection . For evaluation of the chromatograms, the software ChromGate, Version 2.8 (Knauer) was used.In the present study, in contrast to the method of van Dijk et al. , serum wIn several tests, it was established that, by acidification with hydrochloric acid instead of sulfuric acid, and a pH range thus set at between 4.0 and 5.1, the derivatization was completed within 45 min and thus produced maximal measurement signals.The problem described by van Dijk et al.  that theStatistical analysis was performed using univariate analysis of variance to test the effect of group and medication status. The analyses were carried out using SPSS statistical software .In controls and ADHD children the SSAO serum activity Fig.  was withp2 = 0.01; df = 1) and no influence of stimulant medication status .The univariate analysis of variance revealed no differences between children with ADHD  and healthy children   -22 and qReduced quality of measurement underlying the lack of differences could be excluded due to our findings of stable SSAO serum activity in healthy adults  . But sevIn human brain the existence of SSAO is still under consideration . Due to The small effect sizes of aminoxidase differences found in mental disorders, e.g. MAO in schizophrenia , might aThus our negative finding concerning group differences of SSAO serum activity has to be interpreted with some caution because it is difficult to be certain to what extent it may reflect a lack of statistical power to detect small effect sizes.In sum, there is no evidence for a deviation of SSAO serum activity in ADHD. Hence, extracellularly acting SSAO does not seem to be a promising factor for further research in ADHD. But progress in knowledge of its physiologic role and of the relationship between the membrane-bound and the circulating serum form may open new avenues for research on SSAO in ADHD.semicarbazide-sensitive amine oxidase (SSAO)attention deficit hyperactivity disorder (ADHD)monoamine oxidases (MAO)high pressure liquid chromatography (HPLC)electroencephalography (EEG)The author(s) declare that they have no competing interests.VR conceived of the study, participated in its design, recruited half of the patients and drafted the manuscript. HU recruited half of the patients and participated in study coordination. AB performed the statistical analysis. GB carried out the laboratory analyses and helped to draft the manuscript (methods). SB conceived of the study, participated in its design and coordination. AR participated in study coordination and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.