|Year : 2019 | Volume
| Issue : 2 | Page : 95-103
Zinc deficiency in children with attention-deficit hyperactivity disorder
Azza El-Bakry1, Amal M El Safty2, Amany A Abdou1, Omnia R Amin1, Doaa R Ayoub1, Dina Y Afifi1
1 Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Occupational and Environmental Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||24-Mar-2019|
|Date of Acceptance||10-Apr-2019|
|Date of Web Publication||11-Jul-2019|
Dina Y Afifi
Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo, 11562
Source of Support: None, Conflict of Interest: None
Background Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder in children that may persist into adulthood. Insufficient nutritional supply and deficiency of trace elements and other components including various minerals have been suggested to play a role in the development of ADHD symptoms. Zinc in particular was found to be significantly deficient in patients with ADHD compared with healthy controls, so it was concluded that zinc deficiency might play a role in the etiopathogenesis of ADHD.
Objectives The aim of the work is to investigate the association of serum zinc levels with ADHD diagnosis, its symptom domains, and severity.
Patients and methods A total of 75 children aged from 6 to 14 years with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD were enrolled in this study. All children were assessed using Colored Progressive Matrices IQ test, Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime version (K-SADS-PL), the Working Memory Index (WMI) of Wechsler Intelligence Scale for Children (WISC-III), and Conner’s Parent Rating Scale − Revised − Long version (CPRS-R-L). Serum zinc level was measured in all children using atomic absorption spectroscopy.
Results Overall, 52% of children with ADHD (n=39) had forthright zinc deficiency with serum zinc levels less than 60 μg/dl. Five children only had marginal zinc levels, with serum zinc level ranging between 60 and 80 μg/dl. Serum zinc levels were lower in children living in rural areas. Zinc-deficient children showed lower IQ scores than non-zinc-deficient group.
Keywords: attention-deficit hyperactivity disorder, Kiddie Schedule for Affective Disorders and Schizophrenia, zinc
|How to cite this article:|
El-Bakry A, El Safty AM, Abdou AA, Amin OR, Ayoub DR, Afifi DY. Zinc deficiency in children with attention-deficit hyperactivity disorder. Egypt J Psychiatr 2019;40:95-103
|How to cite this URL:|
El-Bakry A, El Safty AM, Abdou AA, Amin OR, Ayoub DR, Afifi DY. Zinc deficiency in children with attention-deficit hyperactivity disorder. Egypt J Psychiatr [serial online] 2019 [cited 2019 Nov 19];40:95-103. Available from: http://new.ejpsy.eg.net/text.asp?2019/40/2/95/262548
| Introduction|| |
Attention-deficit hyperactivity disorder (ADHD) has been a topic of intense scientific research in the past two decades. ADHD is one of the most common childhood neuropsychiatric conditions with an estimated worldwide-pooled prevalence of ∼5.9% in children (Polanczyk et al., 2007; Sambhi and Lepping, 2009; Lange et al., 2017).
Not only is ADHD one of the most common reasons for mental health consultations in children but it is also a disorder that, if not recognized early on and treated, could lead to scholastic failure, school dropout, and low self-esteem. If left untreated, ADHD could increase the risk for delinquency and substance abuse (Barkley, 2006), particularly in the older adolescents (Moina et al., 2007).
ADHD is characterized by symptoms of inattention and impulsivity/hyperactivity to a degree that is inconsistent with the developmental level. ADHD symptoms persist into adulthood in most patients (Barkley, 2006) and are associated with functional impairment and increased risk of depression, substance abuse, and antisocial behavior (Fair et al., 2012).
The Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV) provided updated ADHD criteria (American Psychiatric Association, 2000). It specifies three clinical subtypes of ADHD: predominantly hyperactive, predominantly inattentive, and combined. These subtypes are arrived at through combinations of two primary symptom dimensions: inattention-disorganization and hyperactivity/impulsivity (Milich et al., 2001). Because these symptom domains appear to be an extreme of a behavioral continuum, the symptom dimensions also serve as useful foci to study a different etiology (Nigg, 2006).
The National Survey of Children’s Health in 2011 reported 11% prevalence of ADHD in children aged between 4 and 17 years of age (Visser et al., 2014).
In the recent years, some research into the role of trace elements in enlightening the etiology of ADHD had been conducted (Lange et al., 2017). Most notable among the studies are the ones particularly examining the relationship between zinc and ADHD. Both animal and human studies suggest that involvement of zinc deficiency plays a major role in hyperactivity (Golub et al., 1996(. Some investigators have reported that zinc was found to be significantly deficient in patients with ADHD compared with healthy controls (Mahmoud et al., 2011; Scassellati et al., 2012; Arnold et al., 2013; Ghanizadeh and Berk, 2013). Zinc is an important cofactor for metabolism of relevant neurotransmitters, prostaglandins, and melatonin, and indirectly affects dopamine metabolism. It is necessary for 100 different metalloenzymes and metal–enzyme complexes (Toren et al., 1996), many of them in the central nervous system. It contributes to structure and function of brain (Black, 1998).
One biochemical and physiological role receiving increasing attention is zinc ion release during neuronal activity (Li et al., 2003). Approximately 15% of the brain’s zinc can be found in synaptic vesicles (Lopez-Garcia et al., 2001).
Several researchers reported that zinc is important in dopamine pathway (Krause, 2008). The dopamine transporter has an endogenous high-affinity zinc-binding site on its extracellular surface. The binding of zinc on the dopamine transporter leads to potent inhibition of dopamine reuptake through inhibition of the inward translocation process by enhancement of carrier-mediated dopamine efflux (Meinild et al., 2004).
Owing to the established fact that dysfunction of the dopamine transporter is involved in the pathogenesis of ADHD, many studies suggested that zinc deficiency in zinc-deficient patients with ADHD leads to decreased striatal extracellular dopamine levels. This happens through the disinhibition (acceleration) of the dopamine inward translocation process by inhibition (deceleration) of the carrier-mediated dopamine efflux (Norregaard et al., 1998).
In view of literature, it was hypothesized that in zinc-deficient patients with ADHD, the available zinc-binding sites on the extracellular face of the dopamine transporter are insufficiently occupied, resulting in elevated dopamine transporter activity (reduced inhibition). Thus, it was concluded that zinc deficiency might play a role in the etiopathogenesis of ADHD (Arnold et al., 2011; Scassellati et al., 2012).
In the USA, Arnold et al. (2005) found that in middle-class American children with ADHD, zinc deficiency was positively correlated with more severe symptoms of ADHD. Another Turkish study reported that patients with lower zinc level had higher Conner’s Parent Rating Scale − Revised − Long version (CPRS-R-L) Total, indicating more severe problems. CPRS Hyperactivity score was associated with zinc levels. As zinc is associated with dopamine metabolism, it was speculated that low zinc level might be associated with more significant impairment in dopaminergic transmission in patients with ADHD (Oner et al., 2010).
An overall meta-analysis suggests a significant association between low zinc levels and a diagnosis of ADHD (Arnold and diSilvestro, 2005; Scassellati et al., 2012 and Arnold et al., 2013;Ghanizadeh and Berk, 2013). Salehi et al. (2016) also showed that zinc supplementation as add-on to the main treatment significantly improved the symptoms of ADHD.
| Patients and methods|| |
Children with ADHD were recruited from the child ADHD clinic located in the Center of Social and Preventive Medicine and from Child outpatient clinic located in Kasr Alainy Psychiatric and Addiction hospital. Participants were assessed through the period from September 2014 to January 2016 on a biweekly basis. Three to four patients were recruited per day.
Participants included in this study were 75 patients of both sexes with age limit from 6 to 14 years, fulfilling DSM-IV criteria of ADHD (American Psychiatric Association, 2000), assessed using Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime version (K-SADS-PL). Children with neurological diseases, pervasive developmental disorders, history of head injury with loss of consciousness, sensorimotor handicap, or other chronic medical conditions (renal, hepatic, endocrinal, and respiratory) were excluded from the study. Children who had received zinc supplementation in the past 3 months were excluded as well.
All patients completed the Colored Progressive Matrices IQ test, and children with mental retardation (full scale IQ<70) were excluded. Parents and their children were interviewed by using K-SADS-PL about children’s lifetime (present and past) DSM-IV disorders to confirm ADHD diagnosis and to screen for other possible psychiatric comorbidities.
Parents of children with ADHD completed CPRS. The Working Memory Index (WMI) only of Wechsler Intelligence Scale for Children − 3rd edition (WISC-III) − Arabic Version was applied to all children with ADHD to test their cognitive abilities and attention.
The clinical assessment was done by the researcher. Psychometric assessments were performed by an experienced clinical psychologist. Each assessment lasted on an average of 2 h with both the researcher and the clinical psychologist.
Serum zinc levels were assayed using atomic absorption spectroscopy in the Laboratory of the Department of Occupational and Environmental Medicine, Cairo University.
According to serum zinc level, patients were divided into two groups (zinc-deficient and non-zinc-deficient groups). Zinc-deficient children are those with serum zinc level less than 60 μg/dl according to the laboratory reference range.
The IQ testing of children (Colored Progressive Matrices: Raven’s Colored Progressive Matrices) (Court and Raven, 1990): this test was used in this research for IQ assessment and exclusion of mental retardation. It is quick and practical because of its independence of language and reading and writing skills and the simplicity of its use and interpretation.
- K-SADS-PL (Arabic Version by Moussaet al., 2011(: it is a widely used semistructured diagnostic interview designed to assess current and past episodes of psychopathology in children and adolescents according to DSM-III-R and DSM-IV criteria. It is applied for school children (6–18 years). It was used for all participants to diagnose ADHD and other psychiatric diagnoses. The K-SADS-PL was administered by interviewing the parent(s) and the child, and finally achieving summary ratings.
- The WMI of WISC-III (Wechsler, 1991) (Arabic Version by Ismael and Meleka, 1999(: the WISC is an individually administered intelligence test for children between the ages of 6 and 16 inclusive that can be completed without reading or writing. It includes five primary index scores: the Verbal Comprehension Index, Visual Spatial Index, Fluid Reasoning Index, WMI, and Processing Speed Index. The WMI (formerly known as Freedom from Distractibility Index) of the Arabic version of WISC was the only index used in this study to test participants’ working memory and attention. It includes three subtests (Digit Span-Letter − Number Sequencing − Arithmetic).
- The Arabic version of CPRS-R-L (El-Sheikhet al., 2002): it is a paper-and-pencil screening questionnaire designed to be completed by parents to assist in determining whether children between the ages of 3 and 17 years might have ADHD. It consists of 80 questions, each followed by four choices.
- Serum zinc levels were assayed using atomic absorption spectroscopy in the Laboratory of the Department of Occupational and Environmental Medicine, Cairo University: blood (3 ml) was withdrawn through venipuncture in the arm of children. Samples were taken by a nurse at the Laboratory of The Preventive Medicine building at Abul Reesh, Kasr Alaini, and at child outpatient clinic located in Kasr Alainy Psychiatric and Addiction Hospital.
This research protocol was presented and approved by the Research Ethics Committee and the Scientific Research Committee in the department of Psychiatry, Faculty of Medicine, Cairo University, in June 2014. Consent was taken from patients’ parents after discussing with them the aim of the study and the procedure applied.
Data were coded and entered using the statistical package statistical package for the social science, version 22 (SPSS Inc., Chicago, IL, USA). Data were summarized using mean, SD, median, minimum and maximum in quantitative data and using frequency (count) and relative frequency (%) for categorical data.
Comparisons between quantitative variables were done using the nonparametric Kruskal–Wallis and Mann–Whitney tests. For comparison of serial measurements before and after treatment within each patient, the nonparametric Wilcoxon signed-rank test was used (Chan, 2003a).
For comparing categorical data, χ2-test was performed. Exact test was used instead when the expected frequency is less than 5 (Chan, 2003b). Correlations between quantitative variables were done using Spearman’s correlation coefficient (Chan, 2003c).
| Results|| |
Regarding age of the children, 61.3% were 6–10 years old (n=46), whereas 38.7% of them were 10–14 years old (n=29). The majority were males (72%). Overall, 30.6% of the children had positive family history suggestive of ADHD among their first- and second-degree relatives, that is, sister, brother, and cousin (n=23).
Up to 74.7% of the sample were diagnosed with the combined type of ADHD (n=56), whereas the predominantly inattentive type represented 24% (n=18); only one child was of the predominantly hyperactive/impulsive type. There was a highly statistically significant sex difference among ADHD subtypes, where the combined type of ADHD was more prevalent among males (P=0.009).
Nearly 60.6% of the children had other psychiatric comorbidities (n=50); comorbid psychiatric diagnoses include oppositional defiant disorder in 44% (n=22), learning disabilities (mixed type) in 26% (n=13), primary nocturnal enuresis in 22% (n=11), adjustment disorder with depressed mood in 8% (n=4), adjustment disorder with depressed and anxious mood in 4% (n=2), secondary encopresis in 6%, phonological disorder, obsessive–compulsive disorder, and conduct disorder in 4% (n=2) each, and diurnal enuresis, stuttering, anorexia nervosa, and separation anxiety disorder in 2% each (n=1). From the aforementioned data, we note the overlap between these comorbidities within the same child ([Figure 1]).
|Figure 1 List of psychiatric disorders among children with attention-deficit hyperactivity disorder with psychiatric comorbidities according to (K-SADS-PL). CD, conduct disorder; DE, diurnal enuresis; LD, learning disorder; NE, nocturnal enuresis; OCD, obsessive–compulsive disorder; ODD, oppositional defiant disorder.|
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Half of the sample (52%) had forthright zinc deficiency with serum zinc levels less than 60 μg/dl, whereas 41.3% of them (n=31) had normal serum zinc levels (>80 μg/dl). Five children only had marginal zinc level, with serum zinc level ranging between 60 and 80 μg/dl ([Table 1]).
There was a statistically significant difference in serum zinc level between males and females in the sample, where serum zinc level was lower among males (P=0.03).
There was also statistically significant difference (P=0.024) in serum zinc level regarding residence of the children, where serum zinc levels were lower in children living in rural areas ([Table 2]).
|Table 2 Serum zinc level and residence of children with attention-deficit hyperactivity disorder|
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There was a highly statistical significant difference (P<0.001) between zinc deficient and non-zinc-deficient children with ADHD regarding IQ, where zinc-deficient children showed lower IQ scores than non-zinc-deficient group ([Table 3] and [Figure 2]).
|Table 3 IQ scores of zinc-deficient and non-zinc-deficient children with attention-deficit hyperactivity disorder (as measured by the Colored Progressive Matrices test)|
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|Figure 2 There was a significant positive correlation between serum zinc level and IQ in children with attention-deficit hyperactivity disorder, that is, the higher serum zinc level of the child, the higher his IQ, which indicates that zinc affects different cognitive functions in children with attention-deficit hyperactivity disorder.|
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There was a highly statistically significant difference (P<0.01) between zinc-deficient and non-zinc-deficient children on arithmetic and digit span subtests of Wechsler Intelligence Scale. In addition, there was a significant positive correlation between serum zinc levels and both Arithmetic and Digit-Span subtests of WMI of Wechsler Intelligence Scale.
Regarding serum zinc level and ADHD symptom domains (as measured by CPRS), Oppositional and Perfectionism subscales showed statistically significant differences (P=0.049 and 0.023, respectively) when comparing zinc-deficient and non-zinc-deficient children. Moreover, there was a highly statistical significant difference (P<0.001) on Psychosomatic subscale of Conner’s test.
Statistically significant negative correlations between serum zinc levels and scores of Oppositional, Perfectionism, Psychosomatic subscales, Conner’s Global Index Impulsive, Conner’s Global Index total subscales of CPRS were found (P=0.003,0.014,<0.001, 0.021, and 0.004, respectively) ([Table 4]).
|Table 4 Correlation between serum zinc level and Conner’s subscales scores|
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| Discussion|| |
In this study, the age of the study sample ranged from 6–14 years with a mean of 112.01±25.32 months. This was the age group selected for the study to be able to apply K-SADS −PL, where it should be applied only to school-aged children (6–18 years). Moreover, 14 years was the upper age limit for children in the child ADHD clinic located in the Center of Social and Preventive Medicine and Child outpatient clinic located in Kasr Alainy Psychiatric and Addiction hospital where the study sample was taken.
Children were of both sexes. Males accounted for 72% of the study sample and females for 28%, so the male to female ratio was ∼2.5 : 1, which is consistent with sex differences reported in the literature for patients with ADHD. Sex differences in the rate of ADHD diagnoses is well documented in literature. Male to female ratio is ∼3 : 1 in community-based samples of youth (Willcutt, 2012). Evidence extracted from studies held in different Arab countries also showed a significant association between ADHD and male sex. This review in Arab countries documented male predominance, with a male to female ratio ranging from 1.61 : 1 to 2.5 : 1 (Alharaiwil et al., 2015).
Psychiatric comorbidities were common in children with ADHD. Almost 67% of children with ADHD have at least one other impairing comorbid diagnosis (Larson et al., 2011). This finding was also supported in this study where most children with ADHD (66.6%) had comorbid psychiatric diagnoses. Most children with ADHD (41.3%) with comorbid psychiatric diagnoses had one concurrent diagnosis, 20% of them had with two comorbid diagnoses and 5.3% of them had three comorbid diagnoses. The most common comorbidity among ADHD group of children was oppositional defiant disorder, and this is in line with literature, which states that ADHD frequently co-occurs with externalizing disorders. Overall, 30–50% of individuals meeting the criteria of ADHD also fulfill the criteria for conduct disorder or oppositional defiant disorder (Singh, 2008). Although externalizing problems may occur early in life, they are often assumed to be preceded by ADHD symptoms. Previous research has therefore mainly explored ADHD as a risk for later development of externalizing traits (Klein et al., 2012). Our results are also consistent with results of a previous Egyptian study held among 50 children with ADHD, where 62% (n=31) of children had concurrent psychiatric comorbidities. It also found that the most common psychiatric diagnoses among children with ADHD was oppositional defiant disorder (diagnosed in 61.29% of children) (Dessouki et al., 2013).
Regarding zinc levels, 58.7% of the study population (n=44) were below the laboratory reference range, which was 80–130 μg/dl, denoting prevalent zinc deficiency among children with ADHD in the study sample; 39 children had serum zinc levels less than 60 μg/dl, and five children had marginal zinc deficiency, with serum zinc level ranging between 60 and 80 μg/dl.
These results are in line with data from previous studies suggesting that many children with ADHD have lower than average zinc levels (Arnold and diSilvestro, 2005; Arnold et al., 2011; Mahmoud et al., 2011; Ghanizadeh and Berk, 2013). An overall meta-analysis also suggests a significant association between low zinc levels and a diagnosis of ADHD (Scassellati et al., 2012 and Arnold et al., 2013).
As to residence, although it was difficult to clearly define urban and rural areas in Egypt, serum zinc levels were found significantly lower in children living in rural areas (P=0.024). Moreover, there was a statistically significant difference between zinc-deficient and non-zinc-deficient children with ADHD regarding residence where zinc deficiency was more prevalent in rural areas (P=0.007). This can be explained by difference in dietary intake between children living in rural and urban areas.
Children living in rural areas depend on diets poor in animal protein and rich in plant-derived proteins, like legumes and grains, which contain higher phytate to zinc ratio. Phytate, is a potent indigestible ligand for zinc that prevents its absorption (Sandstead and Freeland-Gravesb, 2014). This can explain for higher frequency of zinc deficiency among this group of children (Fergusson et al., 1993). It is also known that zinc absorption from a diet high in animal protein will be greater than from a diet rich in plant-derived proteins (King and Keen, 1999). Our results are in line with results of another Egyptian study aiming to assess the prevalence of zinc deficiency in urban versus rural areas among 750 primary school children who were randomly selected. The results revealed that children having low serum zinc level were more from rural (19.7% for boys and 18% for girls) than from urban areas (10.7% for boys and 13.2% for girls) (Matter et al., 2004).
Serum zinc levels among children diagnosed with ADHD (combined type) were lower than serum zinc levels among children with ADHD (inattentive type), and it was the lowest in the child diagnosed as having ADHD (hyperactive type(. These results are reinforced by similar findings of a Turkish study that reported a specific linkage of serum zinc level to measures of hyperactivity and impulsiveness, thus explains the prevalence of zinc deficiency among the hyperactive and the combined type of ADHD (Bilici et al., 2004).
In this study, there was a highly statistical significant difference (P<0.001) between zinc-deficient and non-zinc-deficient children with ADHD regarding IQ. However, there is accumulating evidence that confirms that zinc is essential to brain development and function. It is important for neurogenesis, neuronal migration, synaptogenesis, and synaptic plasticity and is found in areas responsible for intellectual functioning (Takeda, 2000; Wainwright and Colombo, 2006; Suh et al., 2009; Khor and Misra, 2012); thus, zinc deficiency causes alterations in attention, deterioration in memory and language, and thus affecting intelligence (Bhatnagar and Taneja, 2001). This was again proved by this study, which also revealed a significant positive correlation between serum zinc levels and two subtests of WMI of Wechsler Intelligence Scale.
To explore the relationship between serum zinc level and oppositional behavior in children with ADHD, a statistically significant negative correlation was found between serum zinc levels and scores of Oppositional subscale of CPRS. This finding is in accordance with results of previous study that found that zinc levels were lower in ADHD with comorbid oppositional defiant disorder (Starobrat-Hermelin, 1998). Another Turkish study showed a significant improvement in oppositional behavior following zinc supplementation (Uckardes et al., 2009).
Previous studies suggested a linkage between serum zinc levels and hyperactivity/impulsivity. In this study, a statistically significant negative correlation was also found between serum zinc levels and the scores of Conner’s Global Index Impulsive subscale of CPRS. A Turkish study also showed that low zinc level was associated with high CPRS Hyperactivity score. This suggests that patients with low levels of zinc might be at increased risk of having higher levels of hyperactivity (Oner et al., 2010).
| Conclusion|| |
Zinc deficiency was prevalent among the study population at hand, where more than half of the children were below the laboratory reference range for zinc. This finding strengthens the notion that ADHD and zinc deficiency were related but not enough to support a causal relationship. Zinc deficiency was more prevalent in rural areas than urban areas.
There was a significant positive correlation between serum zinc level and IQ scores in ADHD children as well as both Arithmetic and Digit span subtests of WMI of Wechsler Intelligence Scale.
Most of children with ADHD had comorbid psychiatric diagnoses. The most common psychiatric comorbidities among children with ADHD were oppositional defiant disorder, learning disabilities, nocturnal enuresis, and adjustment disorders.
The most important limitation of this study was the small sample size, as only one child in the study sample received the diagnosis of predominantly hyperactive type of ADHD.
We counted only on measuring zinc level in serum, which has certain drawbacks, though it is often better to measure zinc level in several different types of specimen to get a more complete picture, such as serum, cells, hair, urine, and even nails. Rates of marginal deficiency, based on a single tissue assay, might be considered a lower-bound estimate.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Alharaiwil NJ, Ali A, Househ MS, Al-Shehri AM, El-Metwally AA (2015). Systematic review of the epidemiology of attention deficit hyperactivity disorder in Arab countries. Neuosciences (Riyadh) 20:137–144.
American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text revision. Washington, DC: American Psychiatric Publishing.
Arnold LE, diSilvestro RA (2005). Zinc in attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 15:619–627.
Arnold LE, Bozzolo H, Hollway J, Cook A, diSilvestro RA, Bozzolo DR et al.
(2005). Serum zinc correlates with parent- and teacher-rated inattention in children with attention deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 15:628–636.
Arnold LE, diSilvestro RA, Bozzolo D, Bozzolo H, Crowl L, Fernandez S et al.
(2011). Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine. J Child Adolesc Psychopharmacol 21:1–19.
Arnold LE, Hurt E, Lofthouse N (2013). Attention-deficit/hyperactivity disorder: dietary and nutritional treatments. Child Adolesc Psychiatr Clin N Am 22:381–402.
Barkley RA (2006). Attention-deficit hyperactivity disorder: a handbook of diagnosis and treatment. London, UK: Guilford Press.
Bhatnagar S, Taneja S (2001). Zinc and cognitive development. Br J Nutr 85:S139–S145.
Bilici M, Yildirim F, Kandil S, Bekaroglu M, Yildirmis S, Deger O et al.
(2004). Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry 28:181–190.
Black MM (1998). Zinc deficiency and child development. Am J Clin Nutr 68 (Suppl):464S–469S.
Chan YH (2003a). Biostatistics102: quantitative data − parametric & non-parametric tests. Singapore Med J 44:391–396.
Chan YH (2003b). Biostatistics 103: qualitative data − tests of independence. Singapore Med J 44:498–503.
Chan YH (2003c). Biostatistics 104: correlational analysis. Singapore Med J 44:614–619.
Court JH, Raven JC (1990). Manual for Raven’s Progressive Matrices and Vocabulary Scales − Section 2: coloured progressive matrices. Oxford, UK: Oxford Psychologists Press.
Dessouki H, ElBakry A, Elsafty A, Zaki HS (2013). Blood lead level and its association with symptoms and severity of ADHD in children [MD thesis]. unpublished manuscript - Beni Suef, Egypt: Beni Suef University.
El-Sheikh M, Sadek A, Omar A, Nahas G (2002). Psychiatric morbidity in first degree relatives of ADHD children. [MD thesis]. Unpublished manuscript - Cairo, Egypt: Ain Shams University.
Fair DA, Bathula D, Nikolas MA, Nigg JT (2012). Distinct neuropsychological subgroups in typically developing youth inform heterogeneity in children with ADHD. Proc Natl Acad Sci USA 109:6769–6774.
Fergusson EL, Gibson RS, Opare-obisaw C, Ounpuu S, Thompson LU, Lehrfeld J (1993). The zinc nutriture of preschool children living in two African countries. J Nutr 123:1487–1496.
Ghanizadeh A, Berk M (2013). Zinc for treating of children and adolescents with attention-deficit hyperactivity disorder: a systematic review of randomized controlled clinical trials. Eur J Clin Nutr 67:122–124.
Golub MS, Takeuchi PT, Keen CL, Hendrickx AG, Gershwin ME (1996). Activity and attention in zinc-deprived adolescent monkeys. Am J Clin Nutr 64:908–915.
Ismael ME, Meleka LK (1999). Wechsler Intelligence Scale for children. Cairo, Egypt: El Nahda Egyptian Bookshop.
Khor GL, Misra S (2012). Micronutrient interventions on cognitive performance of children aged 5–15 years in developing countries. Asia Pac J Clin Nutr 21:476–486.
King JC, Keen CL (1999). Zinc. In: Shils ME, Olsen JAS, Shike M, Ross AC, editors. Modern nutrition in health and disease. 9th ed. Baltimore, MD: Lippincott Williams & Wilkins. pp. 223–239.
Klein R, Manuzza S, Olazagasti MAR, Roizen E, Hutchison JA, Lashua EC, Castellanos FX (2012). Clinical and functional outcome of childhood attention deficit hyperactivity disorder 33 years later. Arch Gen Psychiatry 69:1295–1303.
Krause J (2008). SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder. Expert Rev Neurother 8:611–625.
Lange KW, Hauser J, Lange KM, Makulska-Gertruda E, Nakamura Y, Reissmann A et al.
(2017). The role of nutritional supplements in the treatment of ADHD: what the evidence says. Curr Psychiatry Rep 19:8.
Larson K, Shirley RA, Kahn RS, Halfen N (2011). Pattern of comorbidity functioning and services uses for U.S. children with ADHD. Pediatrics 127:462–470.
Li YV, Hough CJ, Sarvey JM (2003). Do we need zinc to think? Sci STKE 182:19.
Lopez-Garcia C, Molowny A, Ponsoda X, Nacher J, Sancho-Bielsa F (2001). Synaptic zinc in the central nervous system. Rev Neurol 33:341–347.
Mahmoud MM, El-Mazary AA, Maher RM, Saber MM (2011). Zinc, ferritin, magnesium and copper in a group of Egyptian children with attention deficit hyperactivity disorder. Ital J Pediatr 29:37–60.
Matter MK, Samy MA, Shehab DIH, Khairy SA, Hassan HA (2004). Stunted growth and zinc in primary school children in Egypt. J Pediatr Gastroenterol Nutr 39(Suppl 1):S30.
Meinild AK, Sitte HH, Gether U (2004). Zinc potentiates an uncoupled anion conductance associated with the dopamine transporter. J Biol Chem 279:49671–49679.
Milich R, Ballentine AC, Lynam D (2001). ADHD combined type and ADHD predominantly inattentive type are distinct and unrelated disorders. Clin Psychol Sci Pract 8:463–488.
Moina BS, Pelham WE, Gnagy EM, Thompson AL, Marshal MP (2007). Attention deficit hyperactivity disorder risk for heavy drinking and alcohol use disorder is age specific. Alcohol Clin Exp Res 31:643–654.
Moussa S, Emadeldin M, Amer D, Awad MI, Ghanem M, Amin W, Zaki HS, Adel M(2011). Arabic version of Kiddie-Schedule for Affective Disorders and Schizophrenia − Present and Lifetime Version (K-SADS-PL). Unpublished manuscript- Cairo, Egypt: Cairo University.
Nigg JT (2006). What causes ADHD? New York, NY: Guilford Publications.
Norregaard L, Frederiksen D, Nielsen EO, Gether U (1998). Delineation of an endogenous zinc-binding site in the human dopamine transporter. EMBO J 17:4266–4273.
Oner O, Oner P, Bozkurt OH, Odabas E, Keser N, Karadag H, Kızılgün M (2010). Effects of zinc and ferritin levels on parent and teacher reported symptom scores in attention deficit hyperactivity disorder. Child Psychiatry Hum Dev 41:441–447.
Polanczyk G, Silva de Lima M, Horta BL, Biederman J, Rohde LA (2007). The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164:942–948.
Salehi B, Mohammadbeigi A, Sheykholeslam H, Moshiri E, Dorreh F (2016). Omega-3 and zinc supplementation as complementary therapies in children with attention-deficit/hyperactivity disorder. J Res Pharm Pract 5:22–26.
Sambhi RS, Lepping P (2009). Adult ADHD and psychosis: a review of literature and two cases. Clin Neuropsychiatry 6:174–178.
Sandstead HH, Freeland-Gravesb JH (2014). Dietary phytate, zinc and hidden zinc deficiency. J Trace Elem Med Biol 28:414–417.
Scassellati C, Bonvicini C, Faraone SV, Massimo Gennarelli M (2012). Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses. J Am Acad Child Adolesc Psychiatry 51:1003–1019.
Singh I (2008). Beyond polemics: science and ethics of ADHD. Nat Rev Neurosci 9:957–964.
Starobrat-Hermelin B (1998). The effect of deficiency of selected bioelements on hyperactivity in children with certain specified mental disorders. Ann Acad Med Stetin 44:297–314.
Suh SW, Won SJ, Hamby AM, Fan Y, Sheline CT, Tamano H et al.
(2009). Decreased brain zinc availability reduces hippocampal neurogenesis in mice and rats. J Cereb Blood Flow Metab 29:1579–1588.
Takeda A (2000). Movement of zinc and its functional significance in the brain. Brain Res Rev 34:137–148.
Toren P, Elder S, Sela BA, Wolmer L, Weitz W, Inbar D et al.
(1996). Zinc deficiency in attention-deficit hyperactivity disorder. Biol Psychiatry 40:1308–1310.
Uckardes Y, Ozmert EN, Unal F, Yurdakok K (2009). Effects of zinc supplementation on parent and teacher behaviour rating scores in low socioeconomic level Turkish primary school children. Acta Paediatr 98:731–736.
Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM et al.
(2014). Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/ hyperactivity disorder: United States, 2003–2011. J Am Acad Child Adolesc Psychiatry 53:34–46.
Wainwright PE, Colombo J (2006). Nutrition and the development of cognitive functions: interpretation of behavioral studies in animals and human infants. Am J Clin Nutr 84:961–970.
Willcutt EG (2012). The prevalence of DSM-IV attention-deficit hyperactivity disorder: a meta-analytic review. Neurotherpeutics 9:490–499.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]