Attention-Deficit/Hyperactivity Disorder (ADHD) and Obesity: Update 2016

While psychiatric comorbidities of attention-deficit/hyperactivity disorder (ADHD) have been extensively explored, less attention has been paid to somatic conditions possibly associated with this disorder. However, mounting evidence in the last decade pointed to a possible significant association between ADHD and certain somatic conditions, including obesity. This papers provides an update of a previous systematic review on the relationship between obesity and ADHD (Cortese and Vincenzi, Curr Top Behav Neurosci 9:199–218, 2012), focusing on pertinent peer-reviewed empirical papers published since 2012. We conducted a systematic search in PubMed, Ovid, and Web of Knowledge databases (search dates: from January 1st, 2012, to July 16th, 2016). We retained a total of 41 studies, providing information on the prevalence of obesity in individuals with ADHD, focusing on the rates of ADHD in individuals with obesity, or reporting data useful to gain insight into possible mechanisms underlying the putative association between ADHD and obesity. Overall, over the past 4 years, an increasing number of studies have assessed the prevalence of obesity in individuals with ADHD or the rates of ADHD in patients with obesity. Although findings are mixed across individual studies, meta-analytic evidence shows a significant association between ADHD and obesity, regardless of possible confounding factors such as psychiatric comorbidities. An increasing number of studies have also addressed possible mechanisms underlying the link between ADHD and obesity, highlighting the role, among others, of abnormal eating patterns, sedentary lifestyle, and possible common genetic alterations. Importantly, recent longitudinal studies support a causal role of ADHD in contributing to weight gain. The next generation of studies in the field should explore if and to which extent the treatment of comorbid ADHD in individuals with obesity may lead to long-term weight loss, ultimately improving their overall well-being and quality of life.


Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. It is one of the most frequent childhood-onset psychiatric conditions, with an estimated prevalence exceeding 5% in school-age children [1]. It has been reported that impairing symptoms of ADHD persist into adulthood in up to 65% of childhood-onset cases [2], with a prevalence of ADHD in adults estimated at ∼2.5% [3]. Due to its core symptoms and associated disorders/conditions, ADHD imposes an enormous burden on society in terms of psychological dysfunction, adverse vocational outcomes, stress on families, and societal financial costs. The US annual incremental costs of ADHD have been recently estimated at $143-$266 billion This article is part of the Topical Collection on Attention-Deficit Disorder [4], and costs are substantial also in other countries as well (e.g., [5]).
Whereas the comorbidity between ADHD and psychiatric disorders has been extensively explored [6], the association with somatic conditions has received much less attention. However, a mounting body of evidence on the association between neuropsychiatric disorders and medical conditions has emerged in the past years. In particular, there has been a focus on the relationship between ADHD and obesity. Gaining insight into this possible link is highly relevant from a public health perspective, given the epidemic of obesity and the substantial morbidity (including risk for cardiovascular disease, diabetes, and cancer) and increased risk of mortality associated with this condition [7].
Cortese et al. [8••] first systematically reviewed the literature on the relationship between ADHD and obesity in 2008 and updated this initial review in 2012 [9]. Given that the body of research has continuously grown since then, a further update is warranted. In this paper, we review and critically discuss papers on the relationship between ADHD and obesity/overweight published in the last 4 years (2012-2014).

Methods
Although the present paper is not intended to be a systematic review with a formal and quantitative appraisal of the quality of the studies, we performed a systematic search for original peer-reviewed papers in a set of electronic databases, including PubMed, Ovid databases (Medline, PsycINFO, Embase + Embase classic), and ISI Web of Knowledge (Web of Science [Science Citation Index Expanded], Biological Abstracts, Biosis, Food Science and Technology Abstracts). The search terms and syntax for the search in PubMed were (ADHD OR Attention-Deficit/Hyperactivity Disorder OR Attention Deficit Hyperactivity Disorder OR Hyperkinetic Syndrome) AND (obes* OR overweight). The search terms and syntax were adapted for each of the other electronic databases. References from each paper were examined to find additional studies possibly missed in the electronic search.
We searched for studies reporting information on (1) the prevalence of obesity in individuals with ADHD, (2) the prevalence of ADHD in individuals with obesity, (3) possible mechanisms underlying the putative association between ADHD and obesity, and (4) the implications of the possible association between ADHD and obesity for the clinical management of individuals with both conditions. Regarding criteria no. 1 and no. 2, we included only studies that used either a formal diagnosis of ADHD or in which the diagnosis of ADHD was self-reported. In order to avoid possible bias in the estimation of the prevalence of ADHD in individuals with obesity or of obesity in individuals with ADHD, we did not include studies in which participants presented only with ADHD symptoms above a cutoff on any scale for ADHD. However, we did not apply this exclusionary criterion when considering studies on the possible mechanisms linking ADHD and obesity, since a dimensional approach can still be informative in this respect. We did not apply any language restriction. We searched for reports published from January 1st, 2012, to July 16th, 2016.

Results
The search retrieved 3412 potentially pertinent hits. After excluding references not meeting our criteria, we retained a total of 41  studies ( Fig. 1 and Tables 1, 2, and 3). Table 4 reports the references excluded [51][52][53][54][55][56][57], with reasons for exclusion. Of the included references, 17 [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] provided information on the prevalence of obesity in individuals with ADHD, 2 [27,28] included data on the prevalence of ADHD in individuals with obesity, and 28 [12, 19-22, 25, 29-46, 48-50, 58] reported data useful to gain insight into possible mechanisms underlying the putative association between ADHD and obesity (We note that references providing information both on the prevalence of obesity in individuals with ADHD and obesity and on possible mechanisms were counted twice). Of note, none of the retrieved studies addressed the implications of the association between ADHD and obesity for the management of patients with both conditions. Details of the studies retained in our review are presented in Tables 1, 2, and 3, which show first study author, year of publication, country (or countries) where the study was carried out, and study key findings. The results of these studies are reported in the following sections, highlighting how studies published after 2012 advance previous knowledge summarized in Cortese and Vincenzi [9].

Prevalence of Obesity/Overweight in Individuals With ADHD
Cortese and Vincenzi [9] reviewed 12 studies [59][60][61][62][63][64][65][66][67][68][69][70]. Of these, six [61,[63][64][65]69] more specifically compared the rates of obesity/overweight between individuals with ADHD and without ADHD (or from the general population). Overall, Cortese and Vincenzi [9] concluded that studies in both clinical and epidemiological samples suggested that individuals with ADHD have higher than average BMI-SDS or a higher prevalence of obesity compared to non-ADHD subjects. However, one of the drawbacks highlighted by Cortese and Vincenzi [9] was that a sizable portion of studies had not controlled for the possible confounding effect of psychiatric comorbidities, so that it was not possible to establish to which extent the increased rates of obesity/overweight found in individuals with ADHD are accounted for by ADHD per se or by comorbid psychiatric disorders. In our updated search focused on the last 4 years, we found 17 additional studies reporting rates of obesity/overweight in individuals with ADHD. As shown in Table 1, overall findings from these studies are still mixed. While some studies showed significantly higher rates of obesity in individuals with compared to those without ADHD, even after controlling for possible confounding factors, others did not. Additionally, the impact of psychostimulant treatment was not consistent across studies, with some of them showing a significant reduction of the rates of obesity in individuals treated with psychostimulants and others not confirming such finding. However, importantly, given the increasing number of studies, recently, this body of search has been recently meta-analyzed. In fact, currently two meta-analyses have been published by two different groups. In the first meta-analysis, Cortese et al. [71••] pooled 42 studies, including a total of 48,161 ADHD subjects and 679,975 comparison subjects. Cortese et al. [71••] found that a significant association between obesity and ADHD was found for both children (odds ratio = 1.20, 95% CI = 1.05-1.37) and adults (odds ratio = 1.55, 95% CI = 1.32-1.81). The pooled prevalence of obesity was increased by about 70% in adults with ADHD (28.2%, 95% CI = 22.8-34.4) compared with those without ADHD (16.4%, 95% CI = 13. 4-19.9), and by about 40% in children with ADHD (10.3%, 95% CI = 7.9-13.3) compared with those without ADHD (7.4%, 95% CI = 5.4-10.1). Interestingly, the significant association remained when limiting the analysis to studies reporting odds ratio adjusted for possible confounding factors (such as low socioeconomic status, comorbid depression, or comorbid anxiety). Gender, study setting, study country, and study quality did not moderate the association between obesity and ADHD. Additionally, ADHD was also significantly associated with overweight. Importantly, individuals medicated for ADHD were not at higher risk of obesity, suggesting that ADHD pharmacological treatment may exert a protective action on the risk of development of obesity, although the meta-analysis could not prove this assumption. In the second meta-analysis by Nigg et al. [20••], published after the one by Cortese et al. [71••], the authors confirmed a significant association between ADHD and obesity (odd ratio = 1.22 (95% CI = 1.11-1.34), highlighting that the association was larger in adults Participants with persistent ADHD were not significantly more obese than those without childhood ADHD. By contrast, participants with remitted ADHD were significantly more likely to be obese than those without childhood ADHD. The rates of obesity did not significantly differ between participants with persistent and remitted ADHD.

5-17
Boys with ADHD aged 10-17 and girls aged 10-12 were more likely to be overweight than children in the general Dutch population. Younger girls and female teenagers, however, were at lower risk for being overweight. Gungor  10-17 In boys, ADHD was not significantly associated with obesity, even in unadjusted models. In girls, ADHD and obesity were significantly associated considering the age range 14-17 in the unadjusted model.

Prevalence of ADHD in Individuals With Obesity/Overweight
Cortese and Vincenzi [9] presented a total of five studies [72][73][74][75][76] exploring the prevalence of ADHD in individuals referred for specialist treatment of obesity. All these studies, with the exception of Braet et al. [74], reported significantly higher rates of ADHD in individuals with obesity compared to controls (either nonobese or general population). In our update, we located an additional two studies [27,28] both confirming significantly higher rates of ADHD (as categorical diagnosis) in individuals with obesity compared to normal weight controls (Table 2). Of note, the meta-analysis by Cortese et al. [71••] excluded studies of individuals in bariatric clinics because these individuals represent a subsample of severely obese individuals, whereas their meta-analysis focused on the association between ADHD and any degree of obesity.
Taking together the two types of studies (focusing on rates of obesity in individuals with ADHD and on the prevalence ADHD in individuals with obesity, respectively), it is fair to state that evidence supports a bidirectional relationship between ADHD and obesity, irrespective of possible confounding factors.

Studies Suggesting Possible Mechanisms Underlying the Association Between ADHD and Obesity
When Cortese and Vincenzi [9] wrote their review in 2012, there was a paucity of studies addressing the possible mechanisms underlying the association between ADHD and obesity/overweight. Since all the studies that they reviewed on the link between the two conditions were cross-sectional, Cortese and Vincenzi [9] hypothesized three pathways: (1) obesity/overweigh or factors associated with obesity/overweight (such as sleep-disordered breathing) lead to ADHD symptoms, (2) ADHD and obesity are underpinned common biological dysfunction, and (3) ADHD contributes to obesity. Overall, beyond case reports, they only found initial evidence from empirical studies pointing to a role of abnormal eating patterns (including binge eating) mediating a link between ADHD and overweight, possibly supporting hypothesis no. 3 but not excluding hypothesis no. 1 [77][78][79].
Over the past 4 years, there have been remarkable progresses in the understanding of the possible mechanisms linking ADHD and obesity. In fact, we located 28 studies [12, 19-22, 25, 29-46, 48-50, 58] (Table 3). Several of these studies [32,36,[42][43][44]46] provide support to the notion that abnormal eating patterns may contribute to the increased risk of obesity in individuals with ADHD, although the crosssectional nature of the majority of the studies cannot prove causality. Another series of studies has also pointed to a All patients tested at 3, 4, and 5 years At age 4 years, being overweight was associated with higher percentages of ADHD. A higher BMI z-score at age 3 years was related to higher mean scores in hyperactivity problems, peer relationship problems, and total difficulties and to higher percentages for ADHD at age 4 years.
OR odds ratio, aOR adjusted odds ratio, BMI body mass index  Patients in the "emotionally dysregulated/undercontroled" cluster reported significantly more childhood (p = 0.035) and adult (p = 0.004) ADHD symptoms than those in the "resilient/high functioning" cluster. The relationship between ADHD and increased BMI was not statistically significant (χ 2 = 0.591, p > 0.05) After controlling for depressive and anxiety symptoms, neither the number of current inattention symptoms nor the hyperactivity/impulsivity 6-17 Adjusting for sex and age only, ADHD symptoms score severity was significantly and positively associated with television exposure, The presence of ADHD symptoms in individuals with depressive/anxiety disorders did not significantly increase risk for metabolic syndrome.
BMI body mass index a Sample size refers to the German sample possible role of decreased physical activity (less involvement in sport activities) or increased hours/day spent watching TV, in individuals with ADHD compared to controls, as a possible mechanism favoring abnormal weigh gain associated with ADHD [12, 33, 35•, 39, 40, 58]. Additionally, there have been also some studies suggesting that comorbid conduct disorder, in addition to or rather than ADHD core symptoms, might contribute to the link between obesity and ADHD [19,22,25,37,49,50]. This initial insight should be further developed in future research. Moreover, researchers started addressing possible common neurobiological underpinnings of obesity and ADHD. Two studies [29,30] among the ones that we retrieved focused on the genetic mechanisms: the first one [29] suggested a possible role of rs206936 NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3); the second one [30] found a marginally significant association with the FTO SNP rs8050136 gene. Finally, the hypothesis by Cortese and Vincenzi [9] that sleep disruption could be involved in the association between ADHD and obesity has been initially tested and supported [48]. Importantly, in the last 4 years, longitudinal studies have explored the direction of the link between ADHD and obesity. Three studies retrieved in our search showed that ADHD chronologically precedes, and likely contributes to, weigh gain [10, 35•, 49]. However, another study has shown the reverse pattern [28]. It is indeed possible that bidirectional pathways are involved.

Studies on the Clinical Implications of the Association Between ADHD and Obesity
Cortese and Vincenzi [9] cited the study by Levy et al. [80] which provided preliminary evidence showing that the screening and pharmacological treatment of previously overlooked ADHD in adults with refractory obesity leads to beneficial effects on weight gain. Clearly, a possible important confounder of this study is the anorexigenic effect associated with psychostimulants. However, Levy et al. [80] noted that appetite reduction was evident in the first 4-6 weeks of treatment, but then it diminished and vanished in most subjects within 2 months. Therefore, the authors of the study concluded that it is unlikely that the anorexigenic effect of psychostimulants contributed to weight loss at followup, after more than 1 year from the start of treatment. Rather, they highlighted how the pharmacological treatment of ADHD led to "self-directedness, a reduction in novelty seeking, and an increased capacity for persistence," which in turn enhanced adherence to diet and ultimately led to weight loss. However, given the naturalistic design of this study, its conclusions should be considered as preliminary and further replication using more rigorous designs is warranted.
Unfortunately, since then, no other studies have been published directly testing, by means of a randomized design, the effects of ADHD screening and treatment of obesity outcomes. However, evidence from recent studies, including those retrieved in our search (e.g., [31] and [34]), supports the notion that individuals with ADHD pharmacologically treated are not at increased risk of obesity.

Conclusions
Over the past 4 years, there has been an increasing interest for the relationship between ADHD and obesity. Studies that addressed the questions: "Is obesity (or overweight) more frequent in individuals with, compared to those without, ADHD?" or "Is there a significant relationship between ADHD and obesity/overweight?" provide overall mixed findings, likely due to heterogeneity in diagnostic methods for ADHD and obesity, population characteristics (e.g., comorbidities), and medication status. However, meta-analytical evidence controlling for these confounding factors support a significant association between nontreated ADHD and obesity.
Remarkably, in the past 4 years, a large number of studies have contributed to our insight on the factors underlying the links between ADHD and obesity. Such body of research has pointed to the role of abnormal (dysregulated) eating patterns, decreased physical activity, sleep disruption, and psychiatric comorbidities, including conduct disorder. Preliminary evidence has also revealed possible common genetic underpinnings. Importantly, longitudinal studies have been published that show how ADHD may be a risk for the future  [52] No formal ADHD diagnosis Hanc et al. (2012) [53] No data on overweight/obesity Ja (2014) [54] No formal ADHD diagnosis Kerekes et al. (2015) [55] No formal ADHD diagnosis McClure et al. (2012) [56] No formal ADHD diagnosis  [57] Review (treatment) without empirical data a This reference is not counted in the PRISMA flowchart in Fig. 1 since the second empirical study reported in it provides data on the prevalence of obesity in individuals with ADHD development of obesity, although the reverse causal link cannot be ruled out. Given the epidemic of obesity, if ADHD does contribute to it, understanding how and to which extent the treatment of comorbid ADHD in individuals with obesity may lead to long-term weight loss in individuals with obesity, improving adherence to diet programs is fundamental. There is a paucity of studies on this issue and we believe that this should receive further attention in future research. This line of research has ultimately the potential to improve the clinical management and, as a consequence, the quality of individuals with both ADHD and obesity.

Compliance with Ethical Standards
Conflict of Interest Samuele Cortese and Luca Tessari declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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