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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 40  |  Issue : 2  |  Page : 86-94

Effect of zinc supplementation in zinc-deficient children with attention-deficit hyperactivity disorder


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 Submission24-Mar-2019
Date of Acceptance10-Apr-2019
Date of Web Publication11-Jul-2019

Correspondence Address:
Dina Y Afifi
Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo, 11562
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejpsy.ejpsy_10_19

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  Abstract 


Background Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder increasing in prevalence. Although there is limited evidence to support treating ADHD with mineral supplements, research does exist showing that patients with ADHD may have reduced levels of zinc, ferritin, and magnesium. These nutrients have important roles in neurologic function, including involvement in neurotransmitter synthesis. In spite of the good response of many patients with ADHD to stimulant drugs, a substantial percent do not respond to or develop significant side effects from stimulants. For this reason, zinc treatment has been considered to show positive results on various symptoms in ADHD patients with zinc deficiency.
Objectives The aim of this study is to elucidate the effect of zinc supplementation on ADHD symptoms in zinc-deficient ADHD children.
Patients and methods Thirty zinc-deficient children diagnosed with ADHD and on a fixed dose of methylphenidate were enrolled in this study. They were assigned to zinc supplementation (30 mg/day) as gluconate in an open-label follow-up trial for 10 weeks.
Results There was a statistically significant difference among zinc-deficient ADHD children before and after zinc supplementation on all working memory index subtest scores and all Conner’s subscale scores. This result points to the effect of zinc supplementation on ADHD symptom domains.

Keywords: attention-deficit/hyperactivity disorder, K-SADS, trace elements, zinc


How to cite this article:
El-Bakry A, El Safty AM, Abdou AA, Amin OR, Ayoub DR, Afifi DY. Effect of zinc supplementation in zinc-deficient children with attention-deficit hyperactivity disorder. Egypt J Psychiatr 2019;40:86-94

How to cite this URL:
El-Bakry A, El Safty AM, Abdou AA, Amin OR, Ayoub DR, Afifi DY. Effect of zinc supplementation in zinc-deficient children with attention-deficit hyperactivity disorder. Egypt J Psychiatr [serial online] 2019 [cited 2019 Dec 7];40:86-94. Available from: http://new.ejpsy.eg.net/text.asp?2019/40/2/86/262547




  Introduction Top


Attention-deficit/hyperactivity disorder (ADHD) is a very common and heterogeneous childhood-onset psychiatric condition of which the rates have risen over the past few decades and continue to rise. It is characterized by impaired levels of inattention and hyperactivity in more than one setting (Sambhi and Lepping, 2009; Villagomez and Ramtekkar, 2014).

There is a significant social and economic cost associated with ADHD (Birnbaum et al., 2005; Matza et al., 2005), which makes it highly clinically relevant to find adequate treatment. Untreated severe ADHD has a poor prognosis in terms of long-term outcome, including conduct and educational problems (Fergusson et al., 2010) and a strong association with adult antisocial personality disorder, substance misuse, and mood disorders (Simon et al., 2009; Pingault et al., 2013).

By parent report, the percentage of children aged 4–17 taking medication for ADHD was 4.8% in 2007 and 6.1% in 2011 (Visser et al., 2014).

Many parents choose not to start medication for fear of side effects and may seek ‘alternative’ or ‘natural’ treatments. Data from the National Health Interview Study demonstrated that for children aged 7–17, by parent report, 8.9% of children had been diagnosed with ADHD, and of those, 24.7% used at least one type of complementary and alternative medical therapy (Kemper et al., 2013).

Furthermore, it is still unclear why about 15% of ADHD patients do not seem to respond to stimulant medication (Wilens et al., 2002; Spencer, 2004), rendering the treatment of a significant minority of patients difficult and often ineffective.

Methylphenidate, the most commonly used and first-line drug in the treatment of ADHD, exerts its effects by inhibiting the dopamine transporter (Volkow et al., 1998). In fact, its therapeutic effect is probably related to an increase in extracellular levels of dopamine, especially in brain regions with high levels of dopamine transporter such as the striatum and a variety of other brain regions (Volkow et al., 2005; Berridge et al., 2006).

The action of methylphenidate on dopamine transporter and neuroimaging findings demonstrate that ADHD patients have increased striatal dopamine transporter densities and that dopamine transporter density is decreased after treatment with methylphenidate (Madras et al., 2005; Krause, 2008). This indicates that the dopamine transporter plays a major role in ADHD. Furthermore, genetic studies (Rommelse et al., 2008; Gizer et al., 2009; Banaschewski et al., 2010) have suggested that the dopamine transporter gene (DAT1; SLC6A3 locus) may be a susceptibility gene for ADHD.

The dopamine transporter is a presynaptic plasma membrane protein specifically expressed by dopaminergic neurons. It is essential for the maintenance of normal dopamine homeostasis in the synaptic cleft and mediates the action of psychostimulants (Torres, 2006). The dopamine transporter is regulated by zinc (Zn2+), which directly interacts with the transporter protein as a potent noncompetitive blocker of substrate translocation (dopamine transport inward and outward) (Norregaard et al., 1998; Scholze et al., 2002).

The fact that dysfunction of the dopamine transporter is involved in the pathogenesis of ADHD is interesting in the context of studies suggesting the involvement of zinc deficiency in patients with ADHD (Arnold and DiSilvestro, 2005; Khan, 2017).

The studies have shown that the human dopamine transporter contains an endogenous high-affinity zinc-binding site on its extracellular face (Stockner et al., 2013).

The binding of zinc on the dopamine transporter leads to potent inhibition of dopamine reuptake through the inhibition of the inward translocation process by enhancement of carrier-mediated dopamine efflux (facilitated outward/reverse transport; Scholze et al., 2002; Loland et al., 2003; Meinild et al., 2004).

Therefore, it was suggested that zinc nutrition may be important for the treatment of ADHD with psychostimulants, as sufficient zinc levels may aid stimulant response. Essentially, both zinc and methylphenidate enhance the extracellular dopamine level by dopamine transporter inhibition (antagonism), an action responsible for the therapeutic properties of methylphenidate in patients with ADHD (Huber et al., 2007).

It is also most likely that the application of zinc as an adjunct to psychostimulants in zinc-deficient ADHD patients improves the binding of these drugs to the dopamine transporter (Lepping and Huber, 2010). It is assumed that this effect is particularly pronounced in patients with very low zinc levels, that isplasma/serum zinc levels of less than 60 mg/dl (normal about 65–120 mg/dl). In this way, zinc could potentially be used as a therapeutic tool in the treatment of zinc-deficient ADHD patients.

Improving zinc nutritional status might even have a beneficial therapeutic effect on zinc-deficient ADHD patients independent of psychostimulant treatment, as it might improve the response to psychostimulants or, at least, might lower the psychostimulant dose needed to successfully treat ADHD (Arnold et al., 2011).

Two placebo-controlled, Middle-Eastern studies found that zinc as a supplementary medication and/or adjunct to the psychostimulant methylphenidate might be beneficial in the treatment of ADHD (Akhondzadeh et al., 2004; Bilici et al., 2004). Further evidence suggests that an optimal clinical response to psychostimulant (amphetamine) therapy may depend on adequate zinc levels (Arnold et al., 2000).

At present there are only three randomized controlled clinical trials, one which included a community sample and two that included clinical samples (Akhondzadeh et al., 2004; Bilici et al., 2004; Arnold et al., 2011). Of the three studies, one was effective on the total ADHD score (Akhondzadeh et al., 2004); the second was positive on hyperactivity and impulsivity measured by the ADHD Scale and Ankar Conner’s Teacher Questionnaire, but showed no effect on inattentiveness measured by any of these scales (Bilici et al., 2004). The third trial was entirely negative (Arnold et al., 2011).

The present study assesses the adjunctive role of zinc in the treatment of children with ADHD while being treated by a fixed dose of methylphenidate.


  Patients and methods Top


Participants were of both sexes with age limit from 6 to 14 years, recruited from the child ADHD clinic (n=35) located in the Center of Social and Preventive Medicine and from the Child Outpatient Clinic located in Kasr Al-Ainy Psychiatric and Addiction Hospital, Cairo University. The participants were assessed through from September 2014 to January 2016 on a biweekly basis.

Children were fulfilling Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria of ADHD (American Psychiatric Association, 2000) and were assessed using Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS-PL). Parents of children enrolled in this study provided an informed written consent.

Children were with low serum zinc level, that is serum zinc level (<60 μg/dl) according to the laboratory reference range. Serum zinc levels were assayed using atomic absorption spectroscopy in the Laboratory of the Department of Occupational and Environmental Medicine, Cairo University.

Participants were either follow-up cases already on psychostimulants and following up in ADHD clinic, or new cases, assessed for first time and prescribed psychostimulant drugs (methylphenidate in the form of ritalin or concerta) and compliant on medications for a period of at least 8 weeks; so that patients reached the full therapeutic effect of medications. Dose of methylphenidate was kept fixed at around 1 mg/kg for all patients and during the entire course of this study.

Parents of included children completed Conner’s Parent Rating Scale (CPRS). The Working Memory Index of Wechsler Intelligence Scale for Children edition (WISC-III)-Arabic Version only was applied to all ADHD children to test their cognitive abilities and attention. Children receiving nonstimulant medications for the treatment of ADHD or those with neurological diseases, pervasive developmental disorders, head injury with loss of consciousness, sensorimotor handicap, or other chronic medical conditions (renal, hepatic, endocrinal, respiratory, etc.) were excluded. Also, children with mental retardation (full scale IQ<70 on the colored progressive matrices IQ test), or those who had received zinc supplementation in the past 3 months or whose parents refused to give an informed consent were excluded from the study as well.

Procedure

Patients should be compliant on methylphenidate for a period of at least 8 weeks before being assigned zinc supplementation. The dose of methylphenidate was kept fixed at around 1 mg/kg for all patients and during the entire course of this study.

Zinc-deficient ADHD children assigned to zinc supplementation (30 mg/day) in two daily divided doses (15 mg, twice a day) as gluconate in an open-label follow up trial for 10 weeks. They were followed up clinically every 2 weeks (i.e. at baseline, 14, 28, 42, 56, and 70 days after starting zinc supplementation) to ensure their compliance and monitor for side effects. Zinc gluconate was chosen for having less gastrointestinal discomfort than zinc sulfate.

Zinc gluconate tablets (15 mg) were given to parents of ADHD children on each visit to ensure compliance and monitor for possible side effects. Patients’ adherence was assessed by history from children and their parents.

The zinc-deficient ADHD children were reassessed 10 weeks following zinc supplementation using Colored Progressive matrices IQ test, and the WISC-III-Arabic version to assess the effect of zinc supplementation on their attention and cognitive abilities.

Their parents were asked to complete CPRS for the second time to assess the effects of zinc supplementation on their children’s ADHD symptoms.

The clinical psychologist who performed the assessments was blind to these procedures.

A second blood sample was withdrawn from zinc-deficient ADHD children to measure serum zinc level after zinc supplementation for 10 weeks.

Drop-out rate

Five zinc-deficient ADHD children dropped out from the study after first clinical and psychometric assessments. Four of them developed severe gastric upset, so their parents refused to continue taking zinc. A single parent refused to continue and asked to quit from the study. Thirty patients only continued in the study till the end.

Measures

  1. The IQ testing of children (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.
  2. K-SADS-PL (Arabic version by Moussaet al., 2011): It is a widely used semi-structured 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), the child, and finally achieving summary ratings.
  3. The Working Memory Index (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’s (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, and Arithmetic).
  4. The Arabic version of Conner’s Parent Rating Scale-Revised, long version 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 suffer from ADHD. It consists of 80 questions, each followed by four choices.
  5. 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 Al-Ainy and at the Child Outpatient Clinic located in Kasr Al-Ainy Psychiatric and Addiction Hospital.


Ethical considerations

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 analysis

  1. Data were coded and entered using the Statistical Package Statistical Package for the Social Sciences, version 22 (SPSS Inc., Chicgo, Illinois, USA). Data were summarized using mean, SD, median, minimum, and maximum in quantitative data, and using frequency (count) and relative frequency (percentage) for categorical data.
  2. Comparisons between quantitative variables were done using the nonparametric Kruskal–Wallis and Mann–Whitney tests.
  3. For comparison of serial measurements before and after treatment within each patient the nonparametric Wilcoxon signed-rank test was used (Chan, 2003a).
  4. For comparing categorical data, χ2-test was performed. Exact test was used instead when the expected frequency is less than 5 (Chan, 2003b).
  5. Correlations between quantitative variables were done using Spearman’s correlation coefficient (Chan, 2003c).



  Results Top


The mean age of the study sample in this study was 107.64±24.96 months; men were more zinc-deficient than women.

As for residence a highly statistically significant difference (P=0.007) between zinc-deficient and nonzinc-deficient children was found where zinc deficiency was more prevalent in rural areas.

Regarding clinical data there was a highly statistically significant difference (P=0.001) between zinc-deficient and nonzinc-deficient ADHD children as regards ADHD subtype, where the combined and hyperactive types of ADHD were more prevalent among zinc-deficient ADHD group of children.

Also an interesting finding in this study was that we found a highly statistically significant difference (P<0.001) between zinc-deficient and nonzinc-deficient ADHD children as regards methylphenidate preparation where most of zinc-deficient children were on ritalin which is more affordable (cheaper) than concerta; this reflects a significant difference in socioeconomic levels between zinc-deficient and nonzinc-deficient groups of children.

However, there was no statistically significant difference (P=0.407) between children regarding the presence of psychiatric comorbidities.

In the current study, a statistically significant difference (P<0.001) in serum zinc levels of zinc-deficient ADHD children before and after zinc supplementation was found ([Table 1]); this indicates that the serum zinc level increased significantly among the zinc-deficient group after receiving zinc supplementation for a period of 10 weeks; however, serum zinc levels are still below the normal reference ranges.
Table 1 Serum zinc levels before and after zinc supplementation (N=30)

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A statistically significant difference between IQ scores (P=0.001) of zinc-deficient ADHD children before and after zinc supplementation was found ([Table 2]). Also a statistically significant difference between all WMI subtest scores (P<0.05) of zinc-deficient ADHD children before and after zinc supplementation was found ([Table 3]); this indicates that zinc supplementation improved specific cognitive abilities in these children including working memory.
Table 2 IQ before and after zinc supplementation (N=30)

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Table 3 Working Memory Index subtests of Wechsler Intelligence Scale of zinc-deficient attention-deficit hyperactivity disorder children before and after zinc supplementation (N=30)

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In addition, there was a highly statistically significant difference (P<0.001) among zinc-deficient ADHD children before and after zinc supplementation on inattention, hyperactivity, Conner’s ADHD index, Conner’s global index impulsive, Conner’s global index total DSM IV − inattention, DSM IV − hyperactivity, and DSM IV − total subscales of Conner’s test. Rest of the subscales showed a statistically significant difference (P<0.05) except the anxiety–shyness subscale where the difference between both groups was not statistically significant (P=0.077; [Table 4]).
Table 4 Conner’s subscale scores of zinc-deficient attention-deficit hyperactivity disorder children before and after zinc supplementation (N=30)

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In addition, a significant positive correlation between serum zinc levels and IQ scores in ADHD children (P=0.001) as well as on both Arithmetic and Digit Span subtests of WMI of Wechsler Intelligence Scale was found, which indicates that zinc affects different cognitive functions in ADHD children.

While there was a significant negative correlation between serum zinc levels and scores of oppositional, perfectionism, psychosomatic subscale, Conner’s global index impulsive, Conner’s global index total subscales of CPRS (P=0.003, 0.014, <0.001, 0.021, and 0.004, respectively).


  Discussion Top


The present study conducted on 30 zinc-deficient ADHD children aged 6–14 years proved that there was a statistically significant difference (P=0.001) between IQ scores of children before and after zinc supplementation which indicates that zinc supplementation improved specific cognitive abilities in these children.

These results are consistent with a study conducted in Brazil on 36 school children aged 6–9 years that found that zinc supplementation significantly increased the Verbal Intelligence Quotient and Performance Intelligence Quotient on WISC-III. This indicates that school children showed an increase in their abilities in factual knowledge, long-term memory, and recall (Verbal Intelligence Quotient), as well as alertness to detail, visual discrimination, planning, logical thinking, social knowledge, spatial analysis, abstract visual problem solving, visual analysis, and construction of objects (Performance Intelligence Quotient) after zinc supplementation (de Moura et al., 2013).Zinc plays a critical role for different brain functions including attention and working memory. It was suggested that zinc deficiency causes alterations in attention, memory impairment, and a decrease in the capacity to learn (Bhatnagar and Taneja, 2001; Livingstone, 2015). This was supported by the current study that showed that zinc supplementation improved working memory significantly among zinc-deficient ADHD children where there was a statistically significant difference (P<0.05) among zinc-deficient ADHD children before and after zinc supplementation on all working memory index subtest scores.These results are reinforced by similar findings in the literature on the beneficial effects of zinc supplementation on short-term memory in children aged 5–15 years (Bryan et al., 2004; Khor and Misra, 2012). However, negative results were reported in other studies that showed limited effects of zinc interventions on the cognitive performance in zinc-deficient preadolescents (Gogia and Sachdev, 2012; Murray-Kolb et al., 2012).

In this study, a statistically significant negative correlation between serum zinc levels and scores of Conner’s global index total subscale of CPRS was found . Also there was a highly statistically significant difference (P<0.001) among zinc-deficient ADHD children before and after zinc supplementation on most of the subscales of Conner’s test. These findings again prove our study hypothesis about the role of zinc supplementation in improving ADHD symptom domains and severity among zinc-deficient ADHD patients.

It was believed that the beneficial effects of zinc in zinc-deficient ADHD patients might be mediated by dopamine transporter inhibition, resulting in increased extracellular dopamine level in the striatum and thus improving symptoms of ADHD (Akhondzadeh et al., 2004; Bilici et al., 2004). Furthermore, zinc is also basic for the production and modulation of melatonin, which helps regulate dopamine function, supposed to be an important factor in ADHD and its treatment (Chen et al., 1999).

An Iranian study also showed that treatment with zinc sulfate (55 mg/day) for 6 weeks, in a double-blinded and placebo-controlled trial improved the Parent and Teacher Rating Scale scores significantly in ADHD children (Akhondzadeh et al., 2004).

The results of the present study are also comparable to the results of a zinc supplementation double-blinded, placebo controlled Turkish study. It was held among low-income primary school ADHD children where the mean scores of Conner’s Rating Scale for Parents decreased significantly on attention-deficit, hyperactivity, and oppositional behavior after 10 weeks of zinc supplementation (Uckardes et al., 2009). Another Turkish study findings showed that treatment with zinc sulfate for 12 weeks improved hyperactivity, impulsivity, and impaired socialization symptoms of ADHD children; however, unlike our study, it showed no effect on the attention-deficit subscale (Bilici et al., 2004).

On the other hand, our results confirming the efficacy of zinc supplementation in the treatment of ADHD contradicts the results of a previous study that did not support zinc supplementation, either alone or with stimulants, as treatment for ADHD in American children (Arnold et al., 2011).Yet it is prudent to mention that there were many methodological differences between this study and other studies held in the Middle East. The most likely explanation for the success of the Middle East trials and failure of the American one is the difference in diets and soil. It is relevant to mention that in the American study by Arnold et al. (2011) most of the American sample was not deficient in zinc most probably because of the variability of the American diet.

To sum up, the present study shows that IQ, WMI of Wechsler Intelligence Scale, and CPRS scores improved with zinc supplementation for 10 weeks. The efficacy of zinc to obtain a better improvement in children with ADHD seems to support a possible role of zinc deficiency in the etiopathogenesis of ADHD.

However, in this study, we do not want to prove that zinc deficiency is ‘the cause of ADHD’. Rather the present study assessed the adjunctive role of zinc in the treatment of ADHD for the first time in Egypt. Zinc supplementation was found to be effective, cheap, and well tolerated as a supplementary medication in the treatment of Egyptian ADHD children receiving stimulants and have low serum zinc levels.

A number of alternative explanations for these findings could be postulated. Zinc levels could just be markers for some other cause of ADHD, including poor general nutrition, rather than having a direct causative role. Furthermore, zinc levels could be markers of a gene that results in deficient zinc absorption or metabolism and also affects attention but not necessarily through zinc deficiency. In other words, the low zinc level could be an effect rather than a cause.

To wrap up, this open label interventional follow-up study demonstrated that zinc as a supplementary medication might be beneficial in the treatment of children with ADHD. However considering the lack of clear evidence for the effect of zinc on ADHD and the possible effect of zinc on the nervous system, more clinical studies are needed to prove or disprove the effect of zinc as a monotherapy or adjuvant therapy.

Strengths of the study

This is an open label, interventional follow-up study aiming to assess the effect of zinc supplementation on the signs of attention-deficit hyperactivity disorder and cognitive abilities among zinc-deficient patients. Also, it is worth noting that, to our knowledge, there are no zinc supplementation studies that have been published previously in the Arab world and this is considered a point of strength in our study.

Limitations

Lack of establishment of a comparison between the patient group taking only stimulant medications without zinc supplementation and the outcomes of both groups; however, in our study, patients served as their own controls.

Feeding habits of the patients participating in the treatment were a variable that was not kept under control. Failure to standardize other micronutrient intake to ensure appropriate background nutrition, and the failure to consider interaction with essential fatty acids was another limitation. However, we tried to overcome this by including only ADHD children with proven laboratory deficiency of zinc. Pretest and post-test assessments might minimize such limitation.

There might have been a selection bias of participants where participants who were willing to take a chance of receiving a supplement with methylphenidate were enrolled in the study. ADHD children with higher severity and inadequate response to stimulants are those who agreed to participate in the study, thus there was a potential source of bias during selection of the participants.

For this reason, implementing a study after removal of the aforementioned limitations would be recommended.


  Conclusion Top


There was a statistically significant difference among zinc-deficient ADHD children before and after zinc supplementation on all WMI subtest scores and all Conner’s subscale scores. This points to the effect of zinc supplementation on ADHD symptom domains, working memory, and attention.

Zinc as additional therapy in zinc-deficient ADHD patients has the potential to enhance outcome in those who are currently only partially responding to psychostimulants.[51]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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