No Significant Association between the Alpha-2A-Adrenergic Receptor Gene and Treatment Response in Combined or Inattentive Subtypes of Attention-Deficit Hyperactivity Disorder

• Abstract
• Introduction
• Patients and Methods
• Participants
• MPH administration and treatment response
• Neuropsychological assessments
• Genotyping
• Statistical analysis
• Results
• Discussion
• References

Abstract

Introduction:

Given the shortage of pharmacogenetic studies on treatment response according to subtype of attention-deficit hyperactivity disorder (ADHD), we investigated the associations between the MspI and DraI polymorphisms of the alpha-2 A-adrenergic receptor gene (ADRA2A) and treatment response to methylphenidate according to subtype of ADHD.

Methods:

We enrolled 115 medication-naïve children with ADHD into an open label 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical ­Global Impression (CGI), ADHD rating scale, and Continuous Performance Test (CPT) pre- and post-treatment.

Results:

There was no statistically significant association between the MspI or DraI genotypes and the relative frequency of CGI-improvement (CGI-I) 1 or 2 status among any of the groups (all types of ADHD, ADHD-C, or ADHD-I). However, among the children with ADHD-C, those subjects with the C/C genotype at the ADRA2A DraI polymorphism tended to have a CGI-I 1 or 2 status post-treatment (OR=4.45, p=0.045).

Discussion:

The results of this study do not support the association between the the MspI or DraI genotypes and treatment response to methylphenidate in ADHD. However, our results ­suggest that subtypes might influence pharmacogenetic results in ADHD.·

Introduction

Attention-deficit/hyperactivity disorder (ADHD) affects 8–12% of school-aged children [1]. ADHD presents with symptoms of inattention, hyperactivity/impulsivity or both. ADHD has an estimated heritability of approximately 80% and is considered to be a complex, polygenic disorder [2]. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ­classifies ADHD into 3 subtypes: inattentive [ADHD-I], hyperactive/impulsive [ADHD-H], and combined [ADHD-C] [3].

Although the aetiology of ADHD is not fully understood, there is evidence that dysregulation of the central noradrenergic system may be involved in its pathophysiology [4] [5]. It has been suggested that norepinephrine improves attention by stimulating the alpha-2-adrenergic receptors that are present in dopamine-containing neurons, which increases the signal-to-noise ratio of these neurons [6] [7] [8]. Of the several types of alpha-2-adrenergic receptors, the alpha-2 A-adrenergic receptor is the most prevalent noradrenergic receptor in the prefrontal cortex and is suggested to be a key component of the central noradrenergic system [7]. It is therefore important to evaluate whether polymorphisms of the alpha-2 A-adrenergic receptor gene (ADRA2A), located on chromosome 10q24-26, are related to the aetiology of ADHD and treatment response to methylphenidate (MPH).

A-1291 C to G single nucleotide polymorphism (SNP), which creates an MspI site (rs1800544) in the promoter region of the gene [9], and a C to T polymorphism in the 30 untranslated region (30-UTR), known as the DraI site (rs553668) [10], are the 2 major polymorphisms that have been investigated in relation to ADHD. While some previous studies have implicated the rarer G allele at the MspI polymorphsim [11] [12] [13] [14] and the T allele at the DraI polymorphism in the risk for ADHD [13] [15], a recent meta-analysis review of candidate gene studies of ADHD did not reveal a significant association between MspI or DraI poly­morphism and ADHD [16]. However, when taking subtypes into account, Park et al. [14] found a significant relationship between the T allele of the DraI and ADHD-C using the transmission disequilibrium test (P=0.03), but no significant association of the DraI polymorphism with ADHD-I or with both subtypes combined (ADHD-C+ADHD-I) was found. These results suggest that the ADHD subtypes may have acted as potential confounders in the investigation.

Because MPH potentiates dopamine availability in the synapses, many pharmacogenetic studies have focused on dopamine-related genes [17]. Comparatively fewer studies have investigated the effect of noradrenergic gene polymorphisms on treatment response to MPH. Although the presence of the G allele at the ADRA2A MspI polymorphism has been associated with greater improvement from MPH treatment [18] [19], more recent studies have reported that neither the MspI nor the DraI polymorphisms of the ADRA2A was significantly associated with MPH response [20] [21]. The above studies included all subtypes of ADHD, however, possibly contributing to clinical heterogeneity and weakening the investigations.

An association between ADRA2A MspI polymorphism and the treatment effect of methylphenidate in inattentive symptoms was previously suggested in children with ADHD [19]. Da Silva et al. [22] specifically assessed this association in ADHD-I, finding that children and adolescents with the G allele at the MspI polymorphism showed significantly lower inattentive scores after the first month of MPH treatment than subjects without the G allele. However, no published studies have investigated the relationship between the ADRA2A genotypes and the treatment response to MPH in either ADHD-C or ADHD-HI.

Because findings in the literature have so far been inconsistent and influenced to varying degrees by a ADHD subtype, we aimed to investigate the associations between the MspI and DraI polymorphisms of the ADRA2A and treatment response to MPH according to the subtype of ADHD. Since heritability is high for the ADHD-C and ADHD-I subtypes but not ADHD-H [23], we focused on ADHD-C and ADHD-I only.

Patients and Methods

Participants

The participants of the study were stimulant-naive children and adolescents who were recruited from the Department of Psychiatry at the Seoul National University Hospital in Korea and diagnosed with ADHD according to the DSM-IV criteria. Children meeting any of the following criteria were excluded: (i) an IQ score below 70; (ii) past or current neurological disease; or (iii) any evidence of a comorbid psychiatric condition, except oppositional defiant disorder or anxiety disorder if neither required medication. To diagnose ADHD and any comorbid disorders, we used the Korean Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL) [24]. We assessed intellectual abilities using the Korean version of the Wechsler Intelligence Scale for Children (KEDI-WISC) [25]. The Institutional Review Board (IRB) for human subjects at Seoul National University Hospital approved the study, and participants’ parents provided written informed consent prior to enrolment.

MPH administration and treatment response

Participants took part in a prospective 8-week, open-labelled study to achieve symptom relief from MPH. Before treatment, subjects underwent clinical and neuropsychological assessments. The ADHD Rating Scale-IV (ADHD-RS) [26] [27] was completed by the parents of the children, and certified child and adolescent psychiatrists administered the Clinical Global Impressions-Severity (CGI-S) scale [28] [29] [30]. Doses of MPH were titrated depending on symptoms and adverse effects at the 2^nd and 4^th weeks of treatment. At each study visit, we asked the parents about medication compliance. If a subject had skipped medication more than 3 times throughout the total treatment period, he/she was excluded from the study. After 8 weeks, the subjects were evaluated with the same clinical and neuropsychological assessments that were administered at baseline. Global improvement of each patient was assessed on the basis of the investigator-rated Clinical Global Impressions-Improvement (CGI-I) scale [28] [29] [30]. Subjects with scores of 1 (very much improved) or 2 (much improved) on the CGI-I after treatment were classified as ‘good responders’, whereas subjects with scores of 3–7 deemed ‘poor responders’. Both parents and investigators were blind to the results of the ADRA2A genotyping.

Neuropsychological assessments

We used the computer-based Continuous Performance Test (CPT) [31] [32] to measure the neuropsychological functions of the children with ADHD. The 4 variables that were recorded were (i) omission errors (failure to respond to the target), which are commonly interpreted as a measure of inattention; (ii) commission errors (responding inappropriately to the non-target), which are interpreted as a measure of impulsivity; (iii) response times for correct responses to the target, which are interpreted as a measure of information processing and motor response speed; and (iv) the standard deviation of the response times for correct responses to the target (response time variability), which is interpreted as a measure of variability or consistency of attention.

Genotyping

The ADRA2A polymorphisms were genotyped as previously described by Cho et al. [15] with slight modifications. Genomic DNA was extracted from whole blood according to standard protocols. The detection of a single nucleotide polymorphism was based upon analysis of primer extension products that were generated from previously amplified genomic DNA using a chip-based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform (Sequined, California, USA). Details of protocols are available on request.

Statistical analysis

We first determined the allele frequency and then subsequently calculated the Hardy-Weinberg equilibrium using a goodness-of-fit χ² test.

Based on previous ADHD genetic studies [15], the subjects were dichotomized according to whether they possessed the rare allele (recessive model).

Group differences in the continuous clinical variables were evaluated using a t-test for independent samples. Between-group comparisons involving categorical data were assessed using either the χ² test or Fisher’s exact test. To investigate the association between the evaluated genotypes and the treatment response to MPH, the odds ratio (OR) and 95% confidence intervals were derived from a series of logistic regression analyses using “good response” as the main outcome variable. We used the homozygosity of a G allele at the MspI polymorphism or the homozygosity of a C allele at the DraI polymorphism as the principal predictor, after controlling for baseline ARS score, age, gender, and mean dose (mg/kg) of MPH. Paired t-tests were used to compare changes in the values of the continuous variables according to the genotypes. All statistical analyses were performed using SPSS (version 19.0; SPSS Inc., Chicago, IL). The significance level was set at p=0.025 (=0.05/2 SNPs).

Results

This study originally included 132 children and adolescents with ADHD, but 17 of them dropped out before completing the 8-week MPH trial. The remaining 115 (9.1±2.3 years old, M=94, F=21) subjects were included in the statistical analysis. Of the DSM-IV subtypes of ADHD, the combined type was the most common in our sample (61.7%), followed by the inattentive (30.4%) type. The ADHD, hyperactive-impulsive type and the ADHD, not otherwise specified (NOS) type were identified in 2.6% and 5.2% of the sample, respectively. After 8 weeks of treatment, the ADHD-RS of all subjects significantly decreased from 27.2±10.5 at baseline to 12.8±9.0 (t=15.3, p<0.001). The CGI-I of all subjects was 2.4±0.8, indicating a significant improvement in symptoms.

MspI genotype analysis of ADRA2A found a G/G genotype in 51 subjects (44.3%), a C/G genotype in another 51 subjects (44.3%), and a C/C genotype in 13 subjects (11.3%). DraI genotype analysis of ADRA2A found a C/C genotype in 31 subjects (27.0%), a C/T genotype in 56 subjects (48.7%), and a T/T genotype in 28 subjects (24.3%). The distributions of genotypes for the MspI and DraI polymorphisms were consistent with the expected Hardy-Weinberg equilibrium values (P>0.05). Genotype distribution of each subtype of ADHD is shown in [Table 1]. When comparing the frequency of each genotype in ADHD-C and ADHD-I, there was no significant group difference in genotypic distribution (χ²=1.74, p=0.419 for DraI genotype, and χ²=4.51, p=0.105 for MspI genotype).

[Table 2] shows the demographic and clinical characteristics according to the MspI and DraI genotypes of the ADHD subjects that participated in this study. When separated according to whether the subjects had a rare allele (GG vs. GC+CC for MspI and CC vs. CT+TT for DraI), there were no significant group ­differences in terms of age; gender; intelligence; frequency of subtype; baseline ADHD-RS, CGI-S, or CPT scores; or mean dose of methylphenidate (mg/kg). When including only ADHD-C or ADHD-I groups, there was also no significant difference in these baseline characteristics according to MspI or DraI genotypes (See [Supplementary Table 1] [2]).

After 8 weeks of treatment, there were no significant associations between the MspI or DraI genotypes and the relative frequency of having a CGI-I 1 or 2 status among any of the groups (all types of ADHD, ADHD-C, or ADHD-I). However, among the children with ADHD-C, those with the C/C genotype at the ADRA2A DraI polymorphism tended to have a CGI-I 1 or 2 status post-treatment (OR=4.45, p=0.045), after controlling for baseline ARS score, age, gender, and mean dosage (mg/kg) of MPH ([Table 3]). There was no significant group difference in the improvement of total, inattentive, or hyperactive-impulsive scores on the ARS according to the MspI or DraI genotypes in any groups of total ADHD, ADHD-C, or ADHD-I (p>0.05, data are not shown but are available on request).

After 8 weeks of treatment with methylphenidate, ADHD children with the G/G genotype at the MspI polymorphism showed greater improvement in mean response time variability than those with either the C/G or C/C genotypes (t=2.74, p=0.007, d=0.54). When controlling for subtype, ADHD-I subjects with the G/G genotype at the MspI polymorphism showed a trend toward greater improvement in mean response time variability than those with the C/G or C/C genotypes (t=2.91, p=0.036, d=0.79) ([Table 4]).

Discussion

To the best of our knowledge, this is the first study to examine the associations between the ADRA2A genotypes and treatment response to MPH according to subtype of ADHD. In this study, no significant association was found between the MspI or DraI genotypes and treatment response to MPH in any of the groups (all types of ADHD, ADHD-C, or ADHD-I).

Previous studies have reported a relationship between ADRA2A MspI polymorphism and response to methylphenidate in inattentive symptoms in ADHD subjects regardless of subtype [19] as well as in ADHD-I subjects specifically [22]. Inconsistent with previous studies [18] [19] [22], however, we did not find any association between this polymorphism and treatment response based on the CGI-I as well as improvement in the inattentive or total scores on the parent-rated ARS. Our small sample size may have reduced the likelihood of finding statistical significance. However, we found a link between the G/G genotype of MspI polymorphism and improvement in response time variability (a measure of variability or consistency in attention) in the ADHD-I as well as all the subtypes combined. This result is somewhat consistent with previous studies that reported better treatment response in the ADHD subjects with the G allele at the MspI polymorphism [19] [22].

The failure to find any association between the DraI polymorphism of ADRA2A and treatment response in all subtypes combined was consistent with previous studies [20] [21]. However, the ADHD-C subjects with C/C genotypes at the DraI polymorphism tended to have a better response to MPH than those with other genotypes. This result suggests that further pharmacogenetic studies of homogeneous groups, such as those with the same ADHD subtype, are needed.

It should be noted that the association between the ADRA2A genotypes and baseline clinical characteristics such as symptom severity or a comorbid disorder may influence these pharmacogenetic findings because higher baseline severity has been reported to predict a greater treatment response in ADHD subjects [33] [34]. Buitelaar et al. [33] suggested that there may be a greater potential for improvement in more severe compared with less severe patients. In the present study, the ADHD subjects with the G/G genotype of the MspI polymorphism had a higher mean response time variability score pre-treatment than those with the C/G or C/C genotypes (59.90 vs. 54.72). Although this difference was not statistically significant (p=0.152), it could lead to greater improvement in response time variability among ADHD subjects with the G/G genotype compared to those with the C/G or G/G genotypes. Likewise, the ADHD-C subjects with the C/C genotype of the DraI polymorphism showed a non-statistically significant trend towards higher mean CGI-S scores pre-treatment than those with the C/T or T/T genotypes (5.00 vs. 4.71, p=0.137), which could have resulted in a greater treatment response in subjects with the C/C genotype.

Several limitations may have influenced the findings in this study. First, although the frequencies of the ADRA2A polymorphisms in this study were similar to those in previous reports, we did not compare the ADRA2A polymorphisms of ADHD subjects with controls. Second, our study assessed subjects’ treatment response after 8 weeks of MPH therapy. This short-term treatment response may not be the same as a long-term treatment response to MPH. Third, we did not use the investigator- or teacher-rated ARS to measure treatment response. Finally, the sample size of this study was small, which may have prevented us from achieving sufficient statistical power to detect significant group differences; thus, the results should be interpreted carefully.

In conclusion, the results of this study do not support the association between the MspI or DraI genotypes and treatment response to MPH in ADHD. However, our results provide evidence for the possible role of the MspI polymorphism in treatment-related neuropsychological changes, such as improvement in response time variability, and also suggest that subtypes might influence pharmacogenetic results in ADHD. Further studies should continue to elucidate treatment response according to genetic polymorphisms in homogeneous samples.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111523) and the Basic Science Program through the National Research Foundation of Korea (2010-0002283).

• References

• 1 Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366: 237-248
  Search in Google Scholar
• 2 Faraone SV, Biederman J. Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 951-958
  CrossrefPubMedSearch in Google Scholar
• 3 Amerian Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 4^th, Text Revision ed. Washington, DC: Amerian Psychiatric Association; 2000
  Search in Google Scholar
• 4 Biederman J, Spencer T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry 1999; 46: 1234-1242
  CrossrefPubMedSearch in Google Scholar
• 5 Pliszka SR, McCracken JT, Maas JW. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry 1996; 35: 264-272
  CrossrefPubMedSearch in Google Scholar
• 6 Arnsten AF. Stimulants: Therapeutic actions in ADHD. Neuropsychopharmacology 2006; 31: 2376-2383
  CrossrefPubMedSearch in Google Scholar
• 7 Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996; 53: 448-455
  CrossrefPubMedSearch in Google Scholar
• 8 Greene CM, Bellgrove MA, Gill M et al. Noradrenergic genotype predicts lapses in sustained attention. Neuropsychologia 2009; 47: 591-594
  CrossrefPubMedSearch in Google Scholar
• 9 Lario S, Calls J, Cases A et al. MspI identifies a biallelic polymorphism in the promoter region of the alpha 2A-adrenergic receptor gene. Clin Genet 1997; 51: 129-130
  PubMedSearch in Google Scholar
• 10 Hoehe MR, Berrettini WH, Lentes KU. Dra I identifies a two allele DNA polymorphism in the human alpha 2-adrenergic receptor gene (ADRAR), using a 5.5 kb probe (p ADRAR). Nucleic Acids Res 1988; 16: 9070
  CrossrefPubMedSearch in Google Scholar
• 11 Comings DE, Gade-Andavolu R, Gonzalez N et al. Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects. Clinical genetics 1999; 55: 160-172
  CrossrefPubMedSearch in Google Scholar
• 12 Comings DE, Gonzalez NS, Cheng Li SC et al. A “line item” approach to the identification of genes involved in polygenic behavioral disorders: the adrenergic alpha2A (ADRA2A) gene. Am J Med Genet B. Neuropsychiatr Genet 2003; 118B: 110-114
  CrossrefPubMedSearch in Google Scholar
• 13 Roman T, Schmitz M, Polanczyk GV et al. Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder? Am J Med Genet B. Neuropsychiatr Genet 2003; 120B: 116-120
  CrossrefPubMedSearch in Google Scholar
• 14 Park L, Nigg JT, Waldman ID et al. Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. Mol Psychiatry 2005; 10: 572-580
  CrossrefPubMedSearch in Google Scholar
• 15 Cho SC, Kim JW, Kim BN et al. Possible association of the alpha-2A-adrenergic receptor gene with response time variability in attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 957-963
  CrossrefPubMedSearch in Google Scholar
• 16 Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Human Genet 2009; 126: 51-90
  CrossrefPubMedSearch in Google Scholar
• 17 Polanczyk G, Zeni C, Genro JP et al. Attention-deficit/hyperactivity disorder: advancing on pharmacogenomics. Pharmacogenomics 2005; 6: 225-234
  CrossrefPubMedSearch in Google Scholar
• 18 Cheon KA, Cho DY, Koo MS et al. Association between homozygosity of a G allele of the alpha-2a-adrenergic receptor gene and methylphenidate response in Korean children and adolescents with attention-deficit/hyperactivity disorder. Biol Psychiatry 2009; 65: 564-570
  CrossrefPubMedSearch in Google Scholar
• 19 Polanczyk G, Zeni C, Genro JP et al. Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2007; 64: 218-224
  CrossrefPubMedSearch in Google Scholar
• 20 Contini V, Victor MM, Cerqueira CC et al. Adrenergic alpha2A receptor gene is not associated with methylphenidate response in adults with ADHD. Eur Arch Psychiatry Clin Neurosci 2011; 261: 205-211
  CrossrefPubMedSearch in Google Scholar
• 21 Hong SB, Kim JW, Cho SC et al. Dopaminergic and noradrenergic gene polymorphisms and response to methylphenidate in korean children with attention-deficit/hyperactivity disorder: is there an interaction?. J Child Adoles Psychopharmacol 2012; 22: 343-352
  CrossrefPubMedSearch in Google Scholar
• 22 da Silva TL, Pianca TG, Roman T et al. Adrenergic alpha2A receptor gene and response to methylphenidate in attention-deficit/hyperactivity disorder-predominantly inattentive type. J Neural Transm 2008; 115: 341-345
  CrossrefPubMedSearch in Google Scholar
• 23 Willcutt EG, Pennington BF, DeFries JC. Etiology of inattention and hyperactivity/impulsivity in a community sample of twins with learning difficulties. J Abnorm Child psychol 2000; 28: 149-159
  CrossrefPubMedSearch in Google Scholar
• 24 Kim YS, Cheon KA, Kim BN et al. The reliability and validity of Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version- Korean version (K-SADS-PL-K). Yonsei Med J 2004; 45: 81-89
  PubMedSearch in Google Scholar
• 25 Park JR KY, Park HJ. Korean educational developmental institute-Wechsler intelligence scale for children (KEDI-WISC). 2002;
  PubMed
• 26 So YK, Noh JS, Kim YS et al. The reliability and validity of Korean parent and teacher ADHD rating scale. J Korean Neuropsychiatr Assoc 2002; 41: 283-289
  PubMedSearch in Google Scholar
• 27 DuPaul GJ. Parent and teacher ratings of ADHD symptoms – Psychometric properties in a community-based sample. J Clin Child Psychol 1991; 20: 245-253
  CrossrefPubMedSearch in Google Scholar
• 28 Cunningham CE, Siegel LS, Offord DR. A dose-response analysis of the effects of methylphenidate on the peer interactions and simulated classroom performance of ADD children with and without conduct problems. J Child Psychol Psychiatry 1991; 32: 439-452
  CrossrefPubMedSearch in Google Scholar
• 29 National Institute of Mental Health . CGI, Clinical Global Impressions. Chevy Chase, Maryland: National Institute of Mental Health; 1970
  Search in Google Scholar
• 30 Sung YS, Cho SC. The standardization of Korean CGI-I and CGI-S in children. In: Proceedings of Annual Meeting of Korean Neuropsychiatric Association. 1995
  Search in Google Scholar
• 31 Greenberg LM, Waldman ID. Developmental normative data on the test of variables of attention (T.O.V.A.). J Child Psychol Psychiatry, Allied Disciplines 1993; 34: 1019-1030
  CrossrefPubMedSearch in Google Scholar
• 32 Shin MS, Cho S, Chun SY et al. A study of the development and standardization of ADHD Diagnostic System. Korean J Child Adol Psychiatr 2000; 11: 91-99
  PubMedSearch in Google Scholar
• 33 Buitelaar JK, Kooij JJ, Ramos-Quiroga JA et al. Predictors of treatment outcome in adults with ADHD treated with OROS^® methylphenidate. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 554-560
  CrossrefPubMedSearch in Google Scholar
• 34 Tamm L, Trello-Rishel K, Riggs P et al. Predictors of treatment response in adolescents with comorbid substance use disorder and attention-deficit/hyperactivity disorder. J Subst Abuse Treat 2013; 44: 224-230
  CrossrefPubMedSearch in Google Scholar

Correspondence

• References

• 1 Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366: 237-248
  Search in Google Scholar
• 2 Faraone SV, Biederman J. Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 951-958
  CrossrefPubMedSearch in Google Scholar
• 3 Amerian Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 4^th, Text Revision ed. Washington, DC: Amerian Psychiatric Association; 2000
  Search in Google Scholar
• 4 Biederman J, Spencer T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry 1999; 46: 1234-1242
  CrossrefPubMedSearch in Google Scholar
• 5 Pliszka SR, McCracken JT, Maas JW. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry 1996; 35: 264-272
  CrossrefPubMedSearch in Google Scholar
• 6 Arnsten AF. Stimulants: Therapeutic actions in ADHD. Neuropsychopharmacology 2006; 31: 2376-2383
  CrossrefPubMedSearch in Google Scholar
• 7 Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996; 53: 448-455
  CrossrefPubMedSearch in Google Scholar
• 8 Greene CM, Bellgrove MA, Gill M et al. Noradrenergic genotype predicts lapses in sustained attention. Neuropsychologia 2009; 47: 591-594
  CrossrefPubMedSearch in Google Scholar
• 9 Lario S, Calls J, Cases A et al. MspI identifies a biallelic polymorphism in the promoter region of the alpha 2A-adrenergic receptor gene. Clin Genet 1997; 51: 129-130
  PubMedSearch in Google Scholar
• 10 Hoehe MR, Berrettini WH, Lentes KU. Dra I identifies a two allele DNA polymorphism in the human alpha 2-adrenergic receptor gene (ADRAR), using a 5.5 kb probe (p ADRAR). Nucleic Acids Res 1988; 16: 9070
  CrossrefPubMedSearch in Google Scholar
• 11 Comings DE, Gade-Andavolu R, Gonzalez N et al. Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects. Clinical genetics 1999; 55: 160-172
  CrossrefPubMedSearch in Google Scholar
• 12 Comings DE, Gonzalez NS, Cheng Li SC et al. A “line item” approach to the identification of genes involved in polygenic behavioral disorders: the adrenergic alpha2A (ADRA2A) gene. Am J Med Genet B. Neuropsychiatr Genet 2003; 118B: 110-114
  CrossrefPubMedSearch in Google Scholar
• 13 Roman T, Schmitz M, Polanczyk GV et al. Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder? Am J Med Genet B. Neuropsychiatr Genet 2003; 120B: 116-120
  CrossrefPubMedSearch in Google Scholar
• 14 Park L, Nigg JT, Waldman ID et al. Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. Mol Psychiatry 2005; 10: 572-580
  CrossrefPubMedSearch in Google Scholar
• 15 Cho SC, Kim JW, Kim BN et al. Possible association of the alpha-2A-adrenergic receptor gene with response time variability in attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 957-963
  CrossrefPubMedSearch in Google Scholar
• 16 Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Human Genet 2009; 126: 51-90
  CrossrefPubMedSearch in Google Scholar
• 17 Polanczyk G, Zeni C, Genro JP et al. Attention-deficit/hyperactivity disorder: advancing on pharmacogenomics. Pharmacogenomics 2005; 6: 225-234
  CrossrefPubMedSearch in Google Scholar
• 18 Cheon KA, Cho DY, Koo MS et al. Association between homozygosity of a G allele of the alpha-2a-adrenergic receptor gene and methylphenidate response in Korean children and adolescents with attention-deficit/hyperactivity disorder. Biol Psychiatry 2009; 65: 564-570
  CrossrefPubMedSearch in Google Scholar
• 19 Polanczyk G, Zeni C, Genro JP et al. Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2007; 64: 218-224
  CrossrefPubMedSearch in Google Scholar
• 20 Contini V, Victor MM, Cerqueira CC et al. Adrenergic alpha2A receptor gene is not associated with methylphenidate response in adults with ADHD. Eur Arch Psychiatry Clin Neurosci 2011; 261: 205-211
  CrossrefPubMedSearch in Google Scholar
• 21 Hong SB, Kim JW, Cho SC et al. Dopaminergic and noradrenergic gene polymorphisms and response to methylphenidate in korean children with attention-deficit/hyperactivity disorder: is there an interaction?. J Child Adoles Psychopharmacol 2012; 22: 343-352
  CrossrefPubMedSearch in Google Scholar
• 22 da Silva TL, Pianca TG, Roman T et al. Adrenergic alpha2A receptor gene and response to methylphenidate in attention-deficit/hyperactivity disorder-predominantly inattentive type. J Neural Transm 2008; 115: 341-345
  CrossrefPubMedSearch in Google Scholar
• 23 Willcutt EG, Pennington BF, DeFries JC. Etiology of inattention and hyperactivity/impulsivity in a community sample of twins with learning difficulties. J Abnorm Child psychol 2000; 28: 149-159
  CrossrefPubMedSearch in Google Scholar
• 24 Kim YS, Cheon KA, Kim BN et al. The reliability and validity of Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version- Korean version (K-SADS-PL-K). Yonsei Med J 2004; 45: 81-89
  PubMedSearch in Google Scholar
• 25 Park JR KY, Park HJ. Korean educational developmental institute-Wechsler intelligence scale for children (KEDI-WISC). 2002;
  PubMed
• 26 So YK, Noh JS, Kim YS et al. The reliability and validity of Korean parent and teacher ADHD rating scale. J Korean Neuropsychiatr Assoc 2002; 41: 283-289
  PubMedSearch in Google Scholar
• 27 DuPaul GJ. Parent and teacher ratings of ADHD symptoms – Psychometric properties in a community-based sample. J Clin Child Psychol 1991; 20: 245-253
  CrossrefPubMedSearch in Google Scholar
• 28 Cunningham CE, Siegel LS, Offord DR. A dose-response analysis of the effects of methylphenidate on the peer interactions and simulated classroom performance of ADD children with and without conduct problems. J Child Psychol Psychiatry 1991; 32: 439-452
  CrossrefPubMedSearch in Google Scholar
• 29 National Institute of Mental Health . CGI, Clinical Global Impressions. Chevy Chase, Maryland: National Institute of Mental Health; 1970
  Search in Google Scholar
• 30 Sung YS, Cho SC. The standardization of Korean CGI-I and CGI-S in children. In: Proceedings of Annual Meeting of Korean Neuropsychiatric Association. 1995
  Search in Google Scholar
• 31 Greenberg LM, Waldman ID. Developmental normative data on the test of variables of attention (T.O.V.A.). J Child Psychol Psychiatry, Allied Disciplines 1993; 34: 1019-1030
  CrossrefPubMedSearch in Google Scholar
• 32 Shin MS, Cho S, Chun SY et al. A study of the development and standardization of ADHD Diagnostic System. Korean J Child Adol Psychiatr 2000; 11: 91-99
  PubMedSearch in Google Scholar
• 33 Buitelaar JK, Kooij JJ, Ramos-Quiroga JA et al. Predictors of treatment outcome in adults with ADHD treated with OROS^® methylphenidate. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 554-560
  CrossrefPubMedSearch in Google Scholar
• 34 Tamm L, Trello-Rishel K, Riggs P et al. Predictors of treatment response in adolescents with comorbid substance use disorder and attention-deficit/hyperactivity disorder. J Subst Abuse Treat 2013; 44: 224-230
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material