What we do not know about ADHD… yet.

REVIEW URRENT C OPINION

What we do not know about ADHD. . . yet Bridget Kiely a and Andrew Adesman b

Purpose of review This article provides an overview of current controversies in attention-deficit/hyperactivity disorder (ADHD) research, with an emphasis on recent findings that are directly relevant to clinical practice. Recent findings Over the past few years, a number of studies have added key evidence to ongoing debates about the epidemiology, nosology, and treatment of ADHD. Although the causes of the rising prevalence of ADHD in the USA are still not fully understood, recent research suggests that environmental factors and changes to the diagnostic criteria may have played a role. In addition, there continues to be controversy surrounding the clinical diagnosis of ADHD and newly recognized, related conditions such as sluggish cognitive tempo. Recent studies have also challenged previous assumptions about the long-term effects of stimulant treatment on growth, academic achievement, and substance use. Moreover, although most complementary and alternative therapies for ADHD appear to be ineffective, there is emerging evidence supporting the value of fatty acid supplementation. Although these findings are promising, more research is needed on all fronts. Summary Although research has shed light on unanswered questions about the epidemiology, nosology, and treatment of ADHD, much is still not known. An understanding of the most important current controversies in ADHD research may aid pediatricians in clinical decision making and allow them to counsel patients more effectively. Keywords attention-deficit/hyperactivity disorder, complementary and alternative medicine, epidemiology, nosology, stimulants

INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 5–10% of US children [1]. ADHD is characterized by persistent symptoms of inattention or hyperactivity–impulsivity, or a combination of the two, that interfere with functioning. The American Academy of Pediatrics (AAP) recommends that pediatricians evaluate children for this disorder when there is evidence of academic or behavioral problems, along with symptoms of inattention, hyperactivity, or impulsivity [2 ]. Although considerable advances have been made in ADHD research, many questions concerning the epidemiology, cause, diagnosis, and treatment of this complex disorder remain unanswered. This review provides an overview of current controversies in ADHD research that are relevant to clinical practice. &

EPIDEMIOLOGY Research on the epidemiology of ADHD has identified several notable trends. The parent-reported

prevalence of ADHD in the US population has increased since the 1990s, and there is a gender imbalance in ADHD diagnoses [3,4]. The reasons for these epidemiological patterns are not fully understood.

THE ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ‘EPIDEMIC’ Numerous epidemiological studies have found that the prevalence of ADHD in the US has increased over the last 2 decades [3–5]. The causes of this so-called ‘epidemic’ of ADHD continue to be contentious a

Yale University, New Haven, Connecticut and bDivision of Developmental and Behavioral Pediatrics, Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park, New York, USA Correspondence to Andrew Adesman, MD, Division of Developmental and Behavioral Pediatrics, Steven and Alexandra Cohen Children’s Medical Center of New York, 1983 Marcus Avenue, Suite 130, Lake Success, New Hyde Park, NY 11040, USA. Tel: +1 516 802 6100; e-mail: [email protected] Curr Opin Pediatr 2015, 27:395–404 DOI:10.1097/MOP.0000000000000229

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KEY POINTS Although ADHD is one of the most extensively researched developmental disorders, a number of questions concerning the epidemiology, nosology, and treatment of this disorder have not yet been resolved. The causes of several important epidemiological trends – such as the rising prevalence of ADHD and the gender imbalance in ADHD diagnoses – are still not fully understood, but recent research suggests that environmental factors and diagnostic bias may play a role. Although the diagnostic criteria were recently revised in the DSM-V, the categorical diagnosis of ADHD – and, in particular, its relationship to SCT – continues to be the subject of considerable controversy. The long-term effects of stimulant treatment on academic achievement, growth, and substance use continue to be contested. Although there is little evidence to support the value of most complementary and alternative treatments for ADHD, there is emerging evidence that fatty acid supplementation may offer modest benefits as an adjunct treatment for ADHD.

[5,6]. One possibility is that the actual prevalence of ADHD has risen because of environmental factors. Electronic media, such as cartoons and video games, have been identified as possible contributors to ADHD symptoms in children. A longitudinal study that followed roughly 1300 school-age children over a 13-month period found an association between attention problems and time spent with television and video games, even after preexisting attention problems were controlled for [7]. The type of media that children view may also be important; one study found that exposure to violent television or nonviolent entertainment television before age 3 predicted later attention problems, whereas exposure to educational television did not [8]. In light of these findings, limiting entertainment screen time to 1–2 h/day, as is recommended by the AAP, may be prudent. Other environmental factors that have been linked to ADHD include diet, family stress, and exposure to toxins [9–12]. However, the relative contribution of each of these factors to the risk of ADHD is thought to be small, and twin studies suggest that the cause of ADHD has a major genetic component [12]. Thus, the notion that environmental factors have contributed to the recent uptick in the prevalence of ADHD is controversial. Another possibility is that the rate at which ADHD is diagnosed has risen in the absence of an actual increase in the number of cases. Greater 396


awareness of ADHD on the part of clinicians and parents, direct-to-consumer marketing of ADHD medications, and the broadening of the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for ADHD in the 1990s may all have contributed to the recent surge in ADHD diagnoses [6,13,14]. In addition, there is some evidence that ADHD may be systematically overdiagnosed. A 2012 study based on mock clinical vignettes found that 16.7% of clinicians who received a non-ADHD vignette gave an incorrect diagnosis of ADHD [13,15]. However, other studies have failed to find evidence of overdiagnosis [16]. Some have speculated that the prevalence of ADHD will continue to rise because of recent changes to the DSM. The DSM-IV required that children display hyperactive–impulsive or inattentive symptoms causing impairment prior to age 7, whereas the DSM-V – which was released in 2013 – specifies that children must present with symptoms by age 12. This change to the diagnostic criteria may simply codify what clinicians have been doing for years, in which case the prevalence of ADHD may not increase significantly. Alternatively, raising the age cutoff may lead to the recognition of previously excluded cases of ADHD. However, some have voiced concerns that increasing the maximum age of symptom onset will facilitate overdiagnosis by causing normal pubertal behaviors – such as impatience and difficulty resisting temptations – to be mislabeled as symptoms of ADHD [6]. Two major studies to date have evaluated the potential effects of extending the age-of-onset cutoff. A 2014 study based on data from a nationally representative survey of US adolescents found that applying the DSM-V age-of-onset cutoff increased the prevalence of ADHD in the sample to 10.84%, compared with 7.38% when the DSM-IV cutoff was used [17 ]. However, a large prospective study of British children concluded that the effects of extending the age-of-onset cutoff from 7 to 12 were ‘negligible’, raising the absolute prevalence of ADHD in the sample by just 0.1% [18]. Differences in the study design may partly account for these conflicting findings [19]. Overall, the extent to which the DSM-V age cutoff will affect the prevalence of ADHD is not known. &&

MALE PREDOMINANCE Over the past 25 years, there has been a steady increase in the number of girls diagnosed with ADHD; nonetheless, males are still significantly more likely than females to receive an ADHD diagnosis during childhood [4,20,21]. Diagnostic bias may partly explain this trend. Referral rates may Volume 27 Number 3 June 2015


What we do not know about ADHD. . . yet Kiely and Adesman

be higher among males with ADHD as they more frequently exhibit hyperactivity and impulsivity, whereas females often present with symptoms that are less likely to be noticed, such as forgetfulness and disorganization [22,23]. In addition, a recent study found that when clinicians were presented with a description of a child with ADHD symptoms, those who were told that the child was male were significantly more likely to give an ADHD diagnosis than those who were told the child was female [15]. Alternatively, biological factors may predispose males to developing ADHD more frequently than females. Several lines of evidence suggest that sexlinked genes may contribute to ADHD risk. Compared with the general population, deficits in attention and executive function are more prevalent among individuals with sex chromosome abnormalities, such as XYY males and females with Turner’s syndrome (XO) [20,24,25]. Moreover, certain genes on the Y chromosome, such as the SRY gene, have been found to be highly expressed in areas of the rodent brain that contain dense populations of dopaminergic neurons, which have been implicated in the pathophysiology of ADHD [20,26]. These findings suggest that diagnostic bias may not be the only cause of the gender imbalance in ADHD. However, the precise reasons for the male predominance of ADHD continue to be contested.

DIAGNOSIS Although the DSM diagnostic criteria for ADHD were revised in 2013, several important nosological debates remain unresolved. There continues to be disagreement as to whether ADHD should be classified separately from related constructs such as sluggish cognitive tempo (SCT). In addition, a number of recent studies have highlighted the extent to which subjective assessments and arbitrary cutoffs contribute to ADHD diagnoses, raising questions about whether the current approach to categorizing and diagnosing ADHD is optimal. The diagnostic criteria for ADHD may evolve in response to these ongoing debates.

SLUGGISH COGNITIVE TEMPO One of the most interesting controversies centers on the construct of ‘SCT’. SCT refers to a set of symptoms related to hypoactivity in children, including cognitive sluggishness, lethargy, and apathetic behavior [27 ,28–31]. Although SCT is not currently recognized as a DSM-V diagnosis, it has been the subject of academic debate, clinical research, and recent media attention, including an April 2014 article in The New York Times. There &&

continues to be disagreement as to whether SCT represents a real disorder that should be classified separately from ADHD [27 ,30]. SCT overlaps substantially with ADHD. A 2013 cross-sectional study of 1800 US children found that 39% of children who met the DSM-IV criteria for ADHD also had high levels of SCT symptoms, whereas 59% of children with SCT had ADHD [32]. SCT symptoms correlate more strongly with the inattentive ADHD symptom domain than with the hyperactive–impulsive domain. A number of researchers have explored the possibility of incorporating SCT into the diagnostic criteria for ADHD and defining new ADHD subtypes based on the presence of SCT symptoms [33–35]. However, several lines of evidence suggest that SCT is sufficiently different from ADHD to merit recognition as a separate disorder [33,36 ]. Statistical techniques such as factor analysis have revealed that SCT symptoms are more tightly correlated with one another than they are with either the inattentive or the hyperactive–impulsive symptoms of ADHD [27 ,28]. Furthermore, ADHD and SCT may present with different profiles of impairments and comorbidities. Compared with ADHD, SCT symptoms are more strongly associated with internalizing symptoms such as anxiety and depression [27 ,28,32]. In addition, children with SCT symptoms are more likely than those with ADHD only to experience social impairments related to isolation and withdrawal, but are less likely to experience rejection because of aggressive, disruptive behaviors [27 ,36 ]. More work is needed to clarify the extent to which SCT overlaps with and is distinct from ADHD. Almost nothing is known about the cause of SCT, and it is not currently clear whether SCT responds to different treatments than does ADHD [27 ]. Considerable research will need to be done to establish if SCT is indeed a distinct disorder and delineate its relationship to ADHD. &&

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CATEGORICAL VERSUS DIMENSIONAL APPROACHES TO ATTENTION-DEFICIT/ HYPERACTIVITY DISORDER The DSM conceptualizes ADHD as a categorical disorder that is diagnosed based on a six-symptom threshold for inattention or hyperactivity–impulsivity, or both. However, critics of this nosological approach have questioned whether it is appropriate to define ADHD as a discrete diagnostic category. A large Dutch study of maternal-reported problems found that symptoms of inattention were distributed along a severity continuum in the general population, with ADHD children falling on the moderate-to-severe end of this spectrum [37]. The




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neurobiological correlates of ADHD symptoms may also exist along a continuum; a recent longitudinal study found that the rate of cortical thinning was slowest in adolescents with ADHD, intermediate in those with symptoms of hyperactivity and impulsivity that did not meet the full ADHD criteria, and fastest in those with minimal ADHD symptoms [38]. These findings suggest that, from both a biological and a functional perspective, there may not be a clear cut point that separates children who have ADHD from those who do not. Therefore, there may be an element of arbitrariness in the diagnosis of ADHD. In light of these and other findings, some researchers have called for the DSM to be modified to better account for the continuous nature of ADHD symptoms [39–41]. One way to accomplish this would be to replace the categorical diagnosis of ADHD with quantitative, dimensional descriptions of a child’s level of inattention and hyperactivity– impulsivity [42]. However, from a practical standpoint, abandoning the diagnostic category of ADHD could create confusion and complicate decisions about when to provide treatment and services [42]. Another possibility would be to retain the categorical diagnosis of ADHD while also adding dimensional modifiers that account for quantitative differences in clinical characteristics such as symptom counts, degree of impairment, symptom duration, or other features [41]. Overall, there is no clear solution to this complex diagnostic issue. It remains to be seen whether future editions of the DSM will conceptualize ADHD primarily as a categorical or a dimensional disorder.

SUBJECTIVITY Clinicians frequently make use of information from multiple sources – such as teachers and parents – when evaluating children for ADHD. However, numerous studies have found that concordance among reports from different informants for the same child is often modest at best. An analysis of data from the Multimodal Treatment of ADHD (MTA) study of 579 children with combined-type ADHD found a moderate correlation of 0.38–0.40 between maternal and paternal ratings of symptoms of inattention and hyperactivity–impulsivity [43]. Overall, mothers rated their children’s symptoms as significantly more severe than fathers did, and the authors concluded that this discrepancy was clinically meaningful; based on maternal ratings alone, 73% of the sample met the criteria for ADHD, compared with 58% when only paternal ratings were considered [43]. Agreement between parents and teachers tends to be even lower; a study of 6171 398


elementary school children found that the correlation between parent and teacher counts of ADHD symptoms was 0.34 for symptoms of inattention and 0.27 for symptoms of hyperactivity–impulsivity [44]. Similarly, a 2012 study found that the correlation between maternal and teacher-reported scores on the ADHD rating scale-IV was just 0.23 [45]. Collectively, these findings demonstrate that the process of evaluating ADHD symptoms may be somewhat subjective. The association between birth dates and ADHD further highlights the extent to which subjective assessments contribute to ADHD diagnoses. Numerous studies have found that the youngest children in a given grade are most likely to be diagnosed with ADHD [46–48]. In states with a September cutoff for kindergarten eligibility, ADHD diagnoses are most prevalent in August-born children; in states with a December cutoff, November-born children are at the highest risk [46]. In other words, the likelihood that a child will receive an ADHD diagnosis depends not just on measures of absolute impairment but also on the child’s relative maturity within his or her peer group. With respect to ADHD, the boundary between normal and pathologic behavior is context dependent. To the extent that the ability to sit still and pay attention is widely recognized as a benchmark of kindergarten readiness, parents and pediatricians may be tempted to delay kindergarten entry for a 5-year-old child who has difficulty paying attention and sitting still. However, school districts typically discourage this practice; moreover, research suggests that it may be helpful in the short term but lead to other problems for the child down the road. These concerns around diagnostic subjectivity and arbitrariness underscore the need to identify objective methods of evaluating ADHD symptoms. Systems such as the QbTest (QbTech AB, Stockholm, Sweden) and the Quotient ADHD System (Pearson Education Inc., Westford, MA, USA) are marketed as computer-based tools for measuring symptoms of hyperactivity, impulsivity, and inattention that may be used to supplement information obtained from the clinical examination [49,50]. These systems attempt to quantify ADHD symptoms by using infrared cameras to track a child’s motions while he or she completes a continuous performance task on a computer [51]. Teicher et al. [52] administered 1 week of placebo treatment and 1 week each of a low, medium, and high dose of methylphenidate to 11 children with ADHD, and assessed their response to each dose using parent reports and a computerbased system. In 82% of children, the dose that was associated with the greatest improvement on the computer-based measures was also the dose that parents rated as producing the best clinical response Volume 27 Number 3 June 2015



[52]. Another study compared the outcomes of children who were evaluated with a combination of clinical assessment tools and the QbTest to those who were evaluated with clinical assessments alone [53]. The children who were evaluated with the QbTest were less likely to have their diagnosis revised within the next year, suggesting that the QbTest may improve diagnostic robustness. Although these findings are promising, the evidence supporting the use of these systems is still relatively sparse. Although both systems are cleared by the Food and Drug Administration, neither the QbTest nor the Quotient ADHD system is currently recommended by the AAP or the American Psychiatric Association [51].

TREATMENT Stimulants, such as methylphenidate and amphetamine, along with nonstimulants, such as atomoxetine, clonidine, and guanfacine, are generally regarded as well tolerated and effective treatments for ADHD. However, a number of questions remain unanswered concerning the benefits and long-term effects of these medications. In addition, the value of complementary and alternative therapies continues to be controversial.

compared with peers with the same age, initial height, and socioeconomic status [60]. Thus, although several studies suggest that stimulants do not cause significant deficits in adult height, more data are needed to evaluate this claim. Long-term follow-up growth data from the MTA study will likely shed some additional light on this issue when published. Interestingly, there is some evidence that, even in the absence of stimulant use, growth patterns may differ between children with ADHD and unaffected controls [61]. At this time, clinicians should advise families that there may be some initial slowing of growth with stimulant therapy and that it is possible that there may be modest sustained differences from a child’s anticipated adult height if children remain on stimulants for years. The relationship between stimulant use and BMI in children with ADHD has also received considerable research attention. A recent study used longitudinal medical record data from 163 820 children to examine the association between stimulant use and BMI over time [62 ]. The unmedicated ADHD children showed more rapid BMI growth after age 10 compared with controls, whereas those who were medicated had a slower rate of BMI growth initially, which was followed by a ‘rebound’ during adolescence that ultimately caused them to have higher BMIs than their non-ADHD peers [62 ]. These findings suggest that children with ADHD, regardless of their medication status, are heavier than their nonADHD peers, and that medication use may alter the trajectory of BMI growth. Several studies looking at adults have also noted an association between ADHD and BMI. For example, in a study of 6735 adults ages 18–44 years, those with clinical symptoms of ADHD were more likely to be overweight (odds ratio ¼ 1.58) or obese (odds ratio ¼ 1.81) [63]. A 33-year prospective study found that, at a mean age of 41 years, men who had received a childhood diagnosis of ADHD had higher BMIs than their non-ADHD counterparts [64]. Conversely, several studies have noted that ADHD is overrepresented in patients seeking treatment for obesity [65–67]. The reason for this increase in BMI is unclear. As elevated BMI has been linked to symptoms of hyperactivity and impulsivity more than inattention, it has been suggested that this is the result of impulsive eating. In fact, an association between ADHD and eating disorder (i.e., binge eating and bulimia nervosa) has been noted in girls [68,69]. It is hoped that future analyses can better characterize why children with ADHD are at increased risk for excess weight gain and possibly eating disorders. More research is also needed to evaluate the extent to which stimulant use moderates the relationship between ADHD and BMI. &&

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EFFECTS ON GROWTH In recent years, there has been debate over whether stimulant use affects growth. Data from the 3-year follow-up of the MTA study showed that stimulant use was associated with a significant reduction in growth velocity during the first year of treatment [54,55]. By the third year, growth rates were the same in the stimulant-treated and nonstimulanttreated groups, although those treated with stimulants continued to be shorter and lighter overall [54,55]. Consistent with these findings, several other studies have concluded that although stimulants may initially slow growth, these effects attenuate over time [54,56–58]. As most studies to date have not followed participants into adulthood, it is less clear whether final adult height is affected by stimulant treatment. At the 10-year follow-up point of a recent study, when the mean age of participants was 22, no association was found between height and prior stimulant use [59]. Another study that evaluated adult males between the ages of 21 and 23 who had previously been treated with stimulants found no overall differences in height between the control and stimulant-treated groups [54,60]. However, regression analyses showed that those who experienced nausea and vomiting as an initial side-effect were predicted to be 6.6 cm shorter in adulthood




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STIMULANTS AND SUBSTANCE ABUSE Children with ADHD are at an increased risk of abusing drugs and alcohol during adolescence and adulthood [70,71]. This association may be primarily due to the effects of hyperactivity and impulsivity; a prospective study of 1512 children from the Minnesota Twin Family Study found that symptoms of hyperactivity–impulsivity, but not inattention, were independently associated with the development of substance use disorders (SUDs) by age 18. The same study also found that the presence of conduct disorder symptoms between the ages of 11 and 14 predicted later substance abuse [72]. It is not yet clear whether treatment with stimulants affects the risk that a child with ADHD will develop SUD. A 2003 meta-analysis reported that children with ADHD who were treated with stimulant medications were less likely to develop SUD in early adulthood compared with those who did not receive stimulant treatment [73]. However, this finding has not consistently been replicated in more recent studies. A 2013 meta-analysis of 15 longitudinal studies failed to find an association between treatment with stimulants during childhood and later dependence on alcohol, cocaine, marijuana, or nicotine [71]. Moreover, at the 8-year follow-up point of the MTA, no relationship was found between lifetime stimulant use and substance abuse [74]. Some researchers have proposed that there may be yet-unknown subgroups within the ADHD population for whom stimulant treatment is protective against substance abuse [75]. However, more research is needed to explore this hypothesis. Whether or not stimulants are actually protective against SUD, most available evidence suggests that children with ADHD are at an increased risk for SUD based on their diagnosis, not their medical treatment. Pediatricians should routinely screen all adolescents with ADHD for SUD, in accordance with AAP guidelines [76 ]. &

LONG-TERM BENEFITS Children with ADHD are significantly more likely than their typically developing peers to experience academic difficulties [77,78]. Although stimulants have been shown to produce short-term increases in concentration and productivity, it is unclear whether they are associated with improvements in long-term measures of academic achievement such as grade point average and grade retention rates [77]. A 2011 study that examined the grade point averages of 3543 students with ADHD found that students received significantly better grades during marking periods in which they were adherent to 400


their ADHD medication regimens [77,79]. However, data from the 8-year follow-up of the MTA study showed no association between lifetime medication use and grades [77,80]. Studies evaluating the effects of medication use on rates of grade repetition have also produced mixed results. Although two recent studies found that children treated with stimulants were significantly less likely to be retained for at least one grade, no association between medication use and grade retention was found in the 8-year follow-up of the MTA [77,80–82]. A 2007 population-based study also found that stimulant use did not reduce dropout rates among adolescents with ADHD [77,82]. Children with ADHD also tend to perform worse on tests of academic achievement than their unaffected peers [77]. Studies of the effects of long-term stimulant use on standardized test performance have produced mixed results. At the 8-year followup of the MTA, there was an association between medication adherence during the previous year and performance on a standardized math achievement test, although no such association was found for reading and spelling achievement tests [77,80]. Another study of 370 children with ADHD found no significant differences between the stimulanttreated and nontreated groups for reading scores on the California Achievement Test [77,82]. Thus, it is not clear whether prolonged use of stimulants is associated with improved performance on academic achievement tests among children with ADHD. This issue is related to, but separate from, the question of whether taking stimulant medication on the day of a high-stakes examination, such as the SAT, may result in a better score than would have otherwise been achieved. Given the prevalence of medication diversion and illicit stimulant use for academic purposes, understanding the relationship between stimulant use and test performance is relevant both to children who have ADHD and those who do not.

FACTORS ASSOCIATED WITH RESPONSE TO TREATMENT It is not currently clear why some patients with ADHD respond well to treatment whereas others do not. Data from the 14-month follow-up of the MTA showed that several factors – including intelligence quotient (IQ), ADHD severity, parental depressive symptoms, and the presence of a comorbid anxiety disorder – moderated response to treatment [83,84]. The Preschoolers with ADHD Treatment Study found that children with three or more comorbidities were less likely than those with fewer comorbidities to show symptom improvement Volume 27 Number 3 June 2015



on methylphenidate [85]. However, due to the relatively small number of studies on this topic, it is difficult to make generalizations about the clinical characteristics that predict response to treatment. Genetic polymorphisms may also account for differences in medication response [86 ]. Over the past 15 years, researchers have identified variants of several genes – including the dopamine transporter (DAT1) gene, the dopamine receptor D4 (DRD4) gene, the norepinephrine transporter (SLC6A2 or NET1) gene, the adrenergic alpha 2a receptor (ADRA2A) gene, and the catechol-O-methyltransferase (COMT) gene – that may be associated with response to stimulants and atomoxetine [86 ,87– 90]. Although these results are promising, they need to be replicated in larger samples before they can reliably be used to guide clinical decision making [86 ]. In addition, the genetic markers that have been identified to date account for just a fraction of the variation in medication response. Thus, patients who express an interest in commercially available genetic tests for ADHD medication response, such as Assurex Health’s GeneSight ADHD panel or Harmonyx Diagnostics’ Test for ADHD, should be cautioned about the limitations of these tests. Overall, the current state of knowledge leaves physicians with relatively few tools for determining which patients will respond to what treatments. From a practical standpoint, although clinicians and patients may be tempted to take advantage of pharmacogenomic testing to guide medication selection, it is unclear how helpful and accessible these tests will prove. For example, the test offered by Harmonyx Diagnostics is only available from a very limited number of pharmacies at this time and it is unclear if insurance will pay for this type of testing. Although pharmacogenomic testing may potentially prove helpful in terms of predicting clinical response (pharmacodynamics) and metabolism (pharmacokinetics), some parents and professionals may find the additional time and expense do not justify this laboratory test at this time until more is known. In general, stimulants are recommended as the first-line medication for most patients with ADHD, and considerations such as duration of benefit, method of administration, and formulary coverage may further guide medication selection. The presence of comorbid conditions may also influence medication selection. Last, knowing that pharmacogenomics may be predictive in some scenarios, if a pediatrician is choosing a medication for a patient who has a close family member with ADHD that has benefited from medication, it may be prudent to prescribe the same medication that proved effective for that relative (e.g., sibling or parent). &

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VALUE OF ALTERNATIVE TREATMENTS Most complementary and alternative treatments for ADHD have failed to show significant benefits in controlled trials [91]. Supplementation with v-3 and v-6 polyunsaturated fatty acids (PUFAs) may be an exception. While a 2012 Cochrane analysis concluded that ‘overall there is little evidence that [polyunsaturated fatty acid] supplementation provides any benefit for the symptoms of ADHD in children and adolescents’, two other recent metaanalyses concluded that fatty acid supplementation was associated with modest improvements in ADHD symptoms [92–94]. Given these disparate conclusions, additional studies are needed to determine whether certain subgroups within the ADHD population respond better than others to fatty acid supplementation. For example, a 2010 study found that among children with ADHD, those with oppositional behavior and those with fewer symptoms of hyperactivity/impulsivity were most likely to show improvement after taking fatty acid supplements for several months [92,95]. Apart from ADHD subtype and comorbidity, factors such as sex, age and baseline nutritional status also need to be evaluated in terms of response to fatty acids. As supplementation with PUFAs is generally very well tolerated and it meets the ‘SECS’ criterion (safe, easy, cheap, and sensible) suggested by Hurt and Arnold [96], it is likely worth recommending a 3-month trial of PUFA supplements (especially v-3 fatty acids) for children not being treated with stimulants or not benefiting robustly from evidence-based therapies such as stimulant treatment or behavior therapy. Assuming a child does not eat three servings of oily wild ocean fish weekly, Hurt and Arnold [96] recommend between 1 and 2 g of PUFAs (v-3 or v-6, or both), with at least 500 mg of eicosapentaenoic acid daily. As PUFAs are prone to oxidation, they also recommend adequate intake of the antioxidant vitamins (C and E) [96]. Neurofeedback has also been promoted as an effective treatment for ADHD, although studies evaluating its efficacy have produced mixed results. The goal of neurofeedback, which is also known as electroencephalographic biofeedback or neurotherapy, is to train participants to modulate their brain activity. Compared with their normal peers, children with ADHD tend to have higher levels of u (lowfrequency) activity, and lower levels of b (highfrequency) activity on their resting electroencephalographics [97 ]. As b waves are associated with alertness and attentiveness, most neurofeedback programs for ADHD are designed to train participants to decrease their u-to-b wave ratio [97 ]. Over the last decade, a number of randomized clinical trials have found that neurofeedback training


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resulted in a significant reduction in ADHD symptoms [97 ,98–101]. However, many of these studies suffered from major methodological limitations, such as a lack of double blinding [97 ,102]. Moreover, few studies to date have employed a true sham treatment as a control, making it difficult to distinguish the specific effects of neurofeedback from the nonspecific effects of receiving treatment [97 ,102]. Notably, a 2012 feasibility trial that was designed to address these methodological issues found no significant differences between the neurofeedback and sham groups [103]. A similarly well designed feasibility study from 2011 also found that neurofeedback was not associated with better outcomes than the sham treatment [104]. As both of these studies were feasibility trials, their sample sizes were relatively small [97 ]. Thus, larger studies of this kind are needed to definitively determine whether neurofeedback is an effective treatment for ADHD. Hopefully, a somewhat definitive answer to this important question will be available in about 4 years based on the results of a meticulously designed 5-year study that has been funded by the National Institute of Mental Health. The study is a ‘multisite, parallel-group, double-blind randomized comparison of active neurofeedback (n ¼ 108) to sham neurofeedback (n ¼ 72) for up to 38 treatments in a 13-week period, with 6, 13, and 25-month follow-ups, in 180 children aged 7–10 years with ADHD (either inattentive or combined type) [97 ]. This study is unprecedented in many ways. To begin with, it is the first randomized clinical trial of neurofeedback with a sham condition that has a sample large enough to detect a medium effect size (d ¼ 0.5) [97 ]. Second and more importantly, given the history of ‘considerable tension’ in the literature and at conferences between ADHD experts and neurofeedback experts, a collaborative approach was deemed essential to move forward so that ‘the results, whatever they are, will be credible to all’ [97 ]. Thus, the study was designed and is being conducted by ‘The Collaborative Neurofeedback Group’ – a research team that comprises mainstream ADHD scientists and experts in research design ‘to insure credible scientific rigor’, and neurofeedback experts ‘to insure credible and rigorous treatment’ [97 ]. Given how difficult it is to get consensus among experts about the efficacy of novel treatment approaches, this endeavor to collaboratively study neurofeedback in a rigorous and effective way is laudable and should serve as an impetus and example for experts in other areas to come together to address equally contentious differences in opinion about treatment approaches.

CONCLUSION

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Although ADHD has been described as one of the best-researched chronic diseases, many important questions have not been definitively answered. The causes of recent epidemiological trends in ADHD – and of the disorder itself – are still not well understood. In addition, a consensus has not been reached on the optimal diagnostic criteria for ADHD. Moreover, the benefits and long-term effects of medical and complementary therapies for this disorder continue to be debated. These gaps in knowledge hinder the ability of clinicians to effectively recognize and treat ADHD. It is hoped that further research in these areas will lead to advances that may reduce the academic, social, and financial burdens associated with this disorder. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Perou R, Bitsko RH, Blumberg SJ, et al. Mental health surveillance among children – United States, 2005–2011. Morb Mortal Wkly Rep 2013; 62: 1–35. 2. Subcommittee on Attention-Deficit/Hyperactivity, Disorder. ADHD: clinical & practice guideline for the diagnosis, evaluation, and treatment of attentiondeficit/hyperactivity disorder in children and, adolescents. Pediatrics 2011; 128:1–16. These guidelines reflect the most current recommendations from the AAP regarding an evidence-based clinical approach to the assessment and treatment of ADHD of preschool and school-age children through adolescence. 3. Centers for Disease Control and Prevention. ADHD throughout the years. 2013. http://www.cdc.gov/ncbddd/adhd/timeline.html. [Accessed 26 March 2015]. 4. Centers for Disease Control and Prevention. Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children – United States, 2003 and 2007. Morb Mortal Wkly Rep 2010; 59:1439– 1443. 5. Frances A, Batstra L. Why so many epidemics of childhood mental disorder? J Dev Behav Pediatr 2013; 34:291–292. 6. Batstra L, Frances A. DSM-5 further inflates attention deficit hyperactivity disorder. J Nerv Ment Dis 2012; 200:486–488. 7. Swing EL, Gentile DA, Anderson CA, Walsh DA. Television and video game exposure and the development of attention problems. Pediatrics 2010; 126:214–221. 8. Zimmerman FJ, Christakis DA. Associations between content types of early media exposure and subsequent attentional problems. Pediatrics 2007; 120:986–992. 9. Howard AL, Robinson M, Smith GJ, et al. ADHD is associated with a ‘western’ dietary pattern in adolescents. J Atten Disord 2011; 15:403– 411. 10. Froehlich TE, Anixt JS, Loe IM, et al. Update on environmental risk factors for attention-deficit/hyperactivity disorder. Curr Psychiatry Rep 2011; 13:333– 344.

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What we do not know about ADHD. . . yet Kiely and Adesman 11. de Oliveira Pires T, da Silva CMFP, de Assis SG. Association between family environment and attention deficit hyperactivity disorder in children – mothers’ and teachers’ views. BMC Psychiatry 2013; 13:215. 12. Thapar A, Cooper M, Eyre O, Langley K. Practitioner review: what have we learnt about the causes of ADHD? J Child Psychol Psychiatry 2012; 54: 3–16. 13. Thomas R, Mitchell G, Batstra L. Attention-deficit/hyperactivity disorder: are we helping or harming? BMJ 2013; 347:f6172. 14. Thomas CP, Conrad P, Casler R, Goodman E. Trends in the use of psychotropic medications among adolescents, 1994 to 2001. Psychiatr Serv 2006; 57:63–69. 15. Bruchmuller K, Margraf J, Schneider S. Is ADHD diagnosed in accord with diagnostic criteria? Overdiagnosis and influence of client gender on diagnosis. J Consult Clin Psychol 2012; 80:128–138. 16. Sciutto MJ, Eisenberg M. Evaluating the evidence for and against the overdiagnosis of ADHD. J Atten Disord 2007; 11:106–113. 17. Vande Voort J, He J, Jameson N, Merikangas K. Impact of the DSM-5 && attention-deficit/hyperactivity disorder age-of-onset criterion in the U.S. adolescent population. J Am Acad Child Adolesc Psychiatry 2014; 53:736–744. This study, which analyzed cross-sectional data from 1894 children between the ages of 12 and 15, found that changing the age-of-onset cutoff from seven to 12 resulted in a substantial increase in the prevalence of ADHD in the sample (from 7.38 to 10.84%). As one of the only published studies evaluating the potential effects of extending the age-of-onset cutoff, this study makes a valuable contribution to the debate over the epidemiological implications of the new DSM-V criteria for diagnosing ADHD. 18. Polanczyk G, Caspi A, Houts R, et al. Implications of extending the ADHD age-of-onset criterion to age 12: results from a prospectively studied birth cohort. J Am Acad Child Adolesc Psychiatry 2010; 49:210–216. 19. Polanczyk GV, Moffitt TE. How evidence on the developmental nature of attention-deficit/hyperactivity disorder can increase the validity and utility of diagnostic criteria. J Am Acad Child Adolesc Psychiatry 2014; 53:723– 725. 20. Trent S, Davies W. The influence of sex-linked genetic mechanisms on attention and impulsivity. Biol Psychol 2012; 89:1–13. 21. Robison LM, Skaer TL, Sclar DA, Galin RS. Is attention deficit hyperactivity disorder increasing among girls in the US? CNS Drugs 2002; 16:129–137. 22. Quinn PO. Treating adolescent girls and women with ADHD: gender-specific issues. J Clin Psychol 2005; 61:579–587. 23. Rucklidge JJ. Gender differences in attention-deficit/hyperactivity disorder. Psychiatr Clin North Am 2010; 33:357–373. 24. Ross JL, Zeger MP, Kushner H, et al. An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47, XYY syndrome or 47, XXY Klinefelter syndrome. Dev Disabil Res Rev 2009; 15:309–317. 25. Russell HF, Wallis D, Mazzocco MM, et al. Increased prevalence of ADHD in Turner syndrome with no evidence of imprinting effects. J Pediatr Psychol 2006; 31:945–955. 26. Dewing P, Chiang CW, Sinchak K, et al. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol 2006; 16:415–420. 27. Barkley R. Sluggish cognitive tempo (concentration deficit disorder?): cur&& rent status, future directions, and a plea to change the name. J Abnorm Child Psychol 2014; 42:117–125. This excellent review article summarizes the most important recent findings from research on SCT. The author concludes that the evidence is nearing a ‘critical mass that likely supports the conclusion that SCT is a distinct disorder of attention from ADHD’. A notable feature of this review is that it identifies several key directions for future research, emphasizing the need for further study of the cause, treatment, and underlying cognitive deficits associated with SCT. 28. Lee S, Burns GL, Snell J, McBurnett K. Validity of the sluggish cognitive tempo symptom dimension in children: sluggish cognitive tempo and ADHDinattention as distinct symptom dimensions. J Abnorm Child Psychol 2014; 42:7–19. 29. Becker S. Topical review: sluggish cognitive tempo: research findings and relevance for pediatric psychology. J Pediatr Psychol 2013; 38:1051– 1057. 30. Becker SP, Marshall SA, McBurnett K. Sluggish cognitive tempo in abnormal child psychology: an historical overview and introduction to the special section. J Abnorm Child Psychol 2014; 42:1–6. 31. Saxbe C, Barkley RA. The second attention disorder? Sluggish cognitive tempo vs. attention-deficit/hyperactivity disorder: update for clinicians. J Psychiatr Pract 2014; 20:38–49. 32. Barkley RA. Distinguishing sluggish cognitive tempo from ADHD in children and adolescents: executive functioning, impairment, and comorbidity. J Clin Child Adolesc Psychol 2013; 42:161–173. 33. Harrington KM, Waldman ID. Evaluating the utility of sluggish cognitive tempo in discriminating among DSM-IV ADHD subtypes. J Abnorm Child Psychol 2010; 38:173–184. 34. Bauermeister JJ, Matos M, Reina G, et al. Comparison of the DSM-IV combined and inattentive types of ADHD in a school-based sample of Latino/Hispanic children. J Child Psychol Psychiatry 2005; 46:166–179. 35. Todd RD, Rasmussen ER, Wood C, et al. Should sluggish cognitive tempo symptoms be included in the diagnosis of attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 2004; 43:588–597.

36. Willcutt EG, Chhabildas N, Kinnear M, et al. The internal and external validity of sluggish cognitive tempo and its relation with DSM-IV ADHD. J Abnorm Child Psychol 2014; 42:21–35. The aim of this study was to determine whether incorporating symptoms of SCT into the diagnostic criteria for predominantly inattentive ADHD (ADHD-I) could improve the discriminant validity of ADHD-I and combined-type ADHD (ADHD-C). The authors compared an ADHD-C group to an ADHD-I group with elevated SCT symptoms on measures of clinical and neuropsychological functioning. They found that there were few meaningful clinical differences between the ADHD-C group and the ADHD-I with the elevated SCT group. This suggests that incorporating SCT symptoms would not improve the discriminant validity of ADHD subtypes. This study adds important evidence to the debate over whether SCT should be classified separately from ADHD. 37. Lubke GH, Hudziak JJ, Derks EM, et al. Maternal ratings of attention problems in ADHD: evidence for the existence of a continuum. J Am Acad Child Adolesc Psychiatry 2009; 48:1085–1093. 38. Shaw P, Gilliam M, Liverpool M, et al. Cortical development in typically developing children with symptoms of hyperactivity and impulsivity: support for a dimensional view of attention deficit hyperactivity disorder. Am J Psychiatry 2011; 168:143–151. 39. Polanczyk GV. Dimensionality of childhood psychopathology and the challenge of integration into clinical practice. Eur Child Adolesc Psychiatry 2014; 23:183–185. 40. Hudziak JJ, Achenbach TM, Althoff RR, Pine DS. A dimensional approach to developmental psychopathology. Int J Methods Psychiatr Res 2007; 16:S16–S23. 41. Kraemer HC. DSM categories and dimensions in clinical and research contexts. Int J Methods Psychiatr Res 2007; 16:S8–S15. 42. Coghill D, Sonuga-Barke EJS. Annual research review: categories versus dimensions in the classification and conceptualisation of child and adolescent mental disorders – implications of recent empirical study. J Child Psychol Psychiatry 2012; 53:469–489. 43. Langberg JM, Epstein JN, Simon JO, et al. Parent agreement on ratings of children’s attention deficit/hyperactivity disorder and broadband externalizing behaviors. J Emot Behav Disord 2010; 18:41–50. 44. Wolraich ML, Lambert EW, Bickman L, et al. Assessing the impact of parent and teacher agreement on diagnosing attention-deficit hyperactivity disorder. J Dev Behav Pediatr 2004; 25:41–47. 45. Sollie H, Larsson B, Mørch W-T. Comparison of mother, father, and teacher reports of ADHD core symptoms in a sample of child psychiatric outpatients. J Atten Disord 2013; 17:699–710. 46. Elder TE. The importance of relative standards in ADHD diagnoses: evidence based on exact birth dates. J Health Econ 2010; 29:641–656. 47. Morow RL, Garland J, Wright JM, et al. Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children. CMAJ 2012; 184:755–762. 48. Zoega H, Valdimarsdottir UA, Hernandez-Diaz S. Age, academic performance, and stimulant prescribing for ADHD: a nationwide cohort study. Pediatrics 2012; 130:1012–1018. 49. Qbtech AB. QbTest. 2013. https://www.qbtech.com/qbtest.html. [Accessed 26 March 2015]. 50. NCS Pearson I. The Quotient ADHD test: objective data to help inform ADHD management. 2015. http://www.quotient-adhd.com/product/product-overview. [Accessed 26 March, 2015]. 51. Dolgin E. FDA clearance paves way for computerized ADHD monitoring. Nat Med 2014; 20:454–455. 52. Teicher MH, Polcari A, McGreenery CE. Utility of objective measures of activity and attention in the assessment of therapeutic response to stimulants in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2008; 18:265–270. 53. Vogt C, Shameli A. Assessments for attention-deficit hyperactivity disorder: use of objective measurements. Psychiatric Bull 2011; 35:380–383. 54. Faraone SV, Biederman J, Morley CP, Spencer TJ. Effect of stimulants on height and weight: a review of the literature. J Am Acad Child Adolesc Psychiatry 2008; 47:994–1009. 55. Swanson JM, Elliott GR, Greenhill LL, et al. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry 2007; 46:1015–1027. 56. Faraone SV, Giefer EE. Long-term effects of methylphenidate transdermal delivery system treatment of ADHD on growth. J Am Acad Child Adolesc Psychiatry 2007; 46:1138–1147. 57. Lisska MC, Rivkees SA. Daily methylphenidate use slows the growth of children: a community based study. J Pediatr Endocrinol Metab 2003; 16:711–718. 58. Poulton A, Cowell C. Slowing of growth in height and weight on stimulants: a characteristic pattern. J Paediatr Child Health 2003; 39:180–185. 59. Biederman J, Spencer TJ, Monteaux MC, Faraone SV. A naturalistic 10-year prospective study of height and weight in children with attention-deficit hyperactivity disorder grown up: sex and treatment effects. J Pediatr 2010; 157:635–640. 60. Kramer JR, Loney J, Ponto LB, et al. Predictors of adult height and weight in boys treated with methylphenidate for childhood behavior problems. J Am Acad Child Adolesc Psychiatry 2000; 39:517–524. &&




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Office pediatrics 61. Faraone SV, Lecendreux M, Konofal E. Growth dysregulation and ADHD: an epidemiologic study of children in France. J Atten Disord 2012; 16:572– 578. 62. Schwartz BS, Bailey-Davis L, Bandeen-Roche K, et al. Attention deficit && disorder, stimulant use, and childhood body mass index trajectory. Pediatrics 2014; 133:668–676. This important study, which was based on electronic health records from 163 820 children, was the first to use longitudinal data to examine the independent associations of ADHD and stimulant use with BMI trajectories during childhood and adolescence. The study found that unmedicated children with ADHD showed faster BMI growth after age 10 compared with controls, whereas children with ADHD who had been medicated with stimulants showed a slower rate of initial BMI growth, followed by a ‘rebound’ that caused them to be heavier than controls by late adolescence. 63. Pagoto SL, Curtin C, Lemon SC, et al. Association between adult attention deficit/hyperactivity disorder and obesity in the US population. Obesity 2009; 17:539–544. 64. Cortese S, Olazagasti MAR, Klein RG, et al. Obesity in men with childhood ADHD: a 33-year controlled, prospective, follow-up study. Pediatrics 2013; 131:e1731–e1738. 65. Cortese S, Comencini E, Vincenzi B, et al. Attention-deficit/hyperactivity disorder and impairment in executive functions: a barrier to weight loss in individuals with obesity? BMC Psychiatry 2013; 13:1–7. 66. Nazar BP, Pinna CM, Suwwan R, et al. ADHD rate in obese women with binge eating and bulimic behaviors from a weight-loss clinic. J Atten Disord 2012; doi: 10.1177/1087054712455503. [Epub ahead of print] 67. Levy LD, Fleming JP, Klar D. Treatment of refractory obesity in severely obese adults following management of newly diagnosed attention deficit hyperactivity disorder. Int J Obes 2009; 33:326–334. 68. Biederman J, Ball SW, Monuteaux MC, et al. Are girls with ADHD at risk for eating disorders? Results from a controlled, five-year prospective study. J Dev Behav Pediatr 2007; 28:302–307. 69. Mikami AY, Hinshaw SP, Patterson KA, Lee JC. Eating pathology among adolescent girls with attention-deficit/hyperactivity disorder. J Abnorm Psychol 2008; 117:225–235. 70. Lee SS, Humphreys KL, Flory K, et al. Prospective association of childhood attention-deficit/hyperactivity disorder and substance use and abuse/dependence: a meta-analytic review. Clin Psychol Rev 2011; 31:328–341. 71. Humphreys KL, Eng T, Lee SS. Stimulant medication and substance use outcomes: a meta-analysis. JAMA Psychiatry 2013; 70:740–749. 72. Elkins IJ, McGue M, Iacono WG. Prospective effects of attention-deficit/ hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry 2007; 64:1145–1152. 73. Wilens TE, Faraone SV, Biederman J, Gunawardene S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 2003; 111: 179–185. 74. Molina BSG, Hinshaw SP, Arnold LE, et al. Adolescent substance use in the multimodal treatment study of attention-deficit/hyperactivity disorder (ADHD) (MTA) as a function of childhood ADHD, random assignment to childhood treatments, and subsequent medication. J Am Acad Child Adolesc Psychiatry 2013; 52:250–263. 75. Goldstein B. Do stimulants prevent substance use and misuse among youth with attention-deficit/hyperactivity disorder? The answer is still maybe. J Am Acad Child Adolesc Psychiatry 2013; 52:225–227. 76. Harstad E, Levy S. Attention-deficit/hyperactivity disorder and substance & abuse. Pediatrics 2014; 134:293–301. This clinical report from the AAP summarizes the literature on the relationship between ADHD and SUD, and provides ‘practical suggestions for optimizing ADHD care while minimizing misuse, abuse, and diversion of stimulant medication.’ 77. Langberg J, Becker S. Does long-term medication use improve the academic outcomes of youth with attention-deficit/hyperactivity disorder. Clin Child Fam Psychol Rev 2012; 15:215–233. 78. Loe IM, Feldman HM. Academic and educational outcomes of children with ADHD. J Pediatr Psychol 2007; 32:643–654. 79. Marcus SC, Durkin M. Stimulant adherence and academic performance in urban youth with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2011; 50:480–489. 80. Molina BSG, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009; 48:484–500. 81. Biederman J, Monteaux MC, Spencer T, et al. Do stimulants protect against psychiatric disorders in youth with ADHD? A 10-year follow-up study. Pediatrics 2009; 124:71–78. 82. Barbaresi WJ, Katusic SK, Colligan RC, et al. Modifiers of long-term school outcomes for children with attention-deficit/hyperactivity disorder: does treatment with stimulant medication make a difference? Results from a population-based study. J Dev Behav Pediatr 2007; 28:274–287. 83. Hinshaw SP. Moderators and mediators of treatment outcome for youth with ADHD: understanding for whom and how interventions work. Ambul Pediatr 2008; 7:91–100. 84. Owens EB, Hinshaw SP, Arnold LE, et al. Which treatment for whom for ADHD? Moderators of treatment response in the MTA. J Consult Clin Psychol 2003; 71:540–552.

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Volume 27 Number 3 June 2015


What we know but do not understand about nidovirus helicases.

What do We Know about Neonatal Cognition?

Editorial: Keratoconus - What We Do Not Know.

What do mind readers know and what do we know about mind readers?

What We Do and Do Not Know about Teaching Medical Image Interpretation.

Educational apps: what we do and do not know.

What we (don't) know about what we know.

Do We Know What We Do not Know? A Response to Celine Bonnet.

Transmission of Ebola viruses: what we know and what we do not know.

What do we need to know about your NHP?

What do we know by now about the genus Naegleria?

What do we know about implicit false-belief tracking?

Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms?

What do we know about canine osteosarcoma treatment? Review.

What do we know about the safe surgery checklist now?

What do we really know about amyotrophic lateral sclerosis?

Fungal Melanin: What do We Know About Structure?

Vaping and health: what do we know about e-cigarettes?

What Do We Know about Opioids and the Kidney?

What do we know about cancer? A bicentennial perspective.

What do we know about phytotherapy of benign prostatic hyperplasia?

What do we know about gliotransmitter release from astrocytes?

What do we know about pediatric renal microlithiasis?

What do we know about Late Onset Huntington's Disease?