The Metabotropic Glutamate Receptor Subtype 7 rs3792452 Polymorphism Is Associated with the Response to Methylphenidate in Children with Attention-Deficit/Hyperactivity Disorder

Abstract

Objective:

The purpose of this study was to investigate the association between the metabotropic glutamate receptor subtype 7 (mGluR7) gene (GRM7) polymorphism and treatment response to methylphenidate in Korean children with attention-deficit/hyperactivity disorder (ADHD).

Methods:

We enrolled 175 medication-naïve children with ADHD in an open-label 8 week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical Global Impressions (CGI) Scale and the parent version of the ADHD Rating Scale-IV (ADHD-RS) before and after treatment.

Results:

After the 8 week course of methylphenidate, children with the GRM7 rs37952452 polymorphism G/A genotype had a more pronounced response rate to the treatment than did children with the G/G genotype according to the ADHD-RS scores (72.2% vs. 55.4%, respectively; p=0.011) and the more stringent standard of combined ADHD-RS and CGI-Improvement (CGI-I) scores (50.0% vs. 35.3%, respectively; p=0.044).

Conclusions:

The present study suggests that the GRM7 rs37952452 polymorphism may play a role in the treatment response to methylphenidate in children with ADHD. Further studies to evaluate the association between glutamate genes and treatment response to methylphenidate in children with ADHD, including a replication of our findings using a control or comparative group in a larger sample, are warranted.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in selective attention, sustained attention, and inhibitory control (Biederman and Faraone 2005). The behavioral and cognitive deficits of ADHD, which have been attributed, in part, to dysfunctional neural reinforcement mechanisms, have been widely hypothesized to originate in dysfunctions in the dopaminergic system. Abnormal dopamine functioning may be the result of a primary defect in dopamine neurons (neuronal firing, dopamine transport, synthesis, receptor functioning) and/or an indirect result of impaired glutamate and/or noradrenergic regulation of dopamine neurons (Volkow et al. 2007).

Psychostimulants, particularly methylphenidate (MPH), constitute the first-line pharmacotherapy for patients with ADHD. Several previous studies have investigated the association between genetic factors and response to MPH and have produced mixed results (Stein and McGough 2008; Froehlich et al. 2010). To avoid the pitfalls associated with small candidate-gene studies, Mick et al. (2008) conducted a genome-wide association study (GWAS) of the treatment response to MPH in 187 children with ADHD. Although the authors failed to find a significant association between markers and treatment response, they did find evidence suggestive of an association with Single nucleotide polymorphisms (SNPs), possibly implicating some novel genes in the MPH response: An armadillo/beta-catenin-like domain gene (ARMC3), sorting nexin 29 (SNX29), a member of the junctophilin family (JPH2), growth arrest-specific 7 (GAS7), holocarboxylase synthetase (HLCS), and a metabotropic glutamate receptor subtype 7 (mGluR7) gene (GRM7). Of these, the most intriguing was the GRM7 gene, which is involved in inhibitory G-protein-coupled signaling and subsequent reduction in cyclic adenosine monophosphate (AMP) levels, because it is widely expressed in the cerebral cortex, hippocampus, and cerebellum, and structural differences in these areas have been associated with ADHD (Kinoshita et al. 1998; Kosinski et al. 1999). However, the association between treatment response and the GRM7 genotype has not been replicated in other populations.

The therapeutic effects of MPH are thought to be mediated by the increase in the synaptic concentrations of dopamine and noradrenaline that it induces by blocking dopamine and noradrenaline transporters, respectively. The main action primarily involves dopamine transporters (Leonard et al. 2004). Prefrontal glutamatergic afferents have been reported to modulate dopaminergic neurons in the nucleus accumbens and ventral tegmental area (Imperato et al. 1990). Glutamate may be involved in the action of methylphenidate via its effect on regulation of dopamine neurons (Kalivas, 2000; Volkow et al. 2007).

Based on the findings of the GWAS (Mick et al. 2008), which suggested a role for the GRM7 rs3792452 polymorphism in the MPH response and the possible involvement of the glutamate pathway in the action of MPH, we investigated the association between the GRM7 rs3792452 polymorphism and treatment responses to MPH in Korean children with ADHD.

Methods

Participants

Participants were stimulant-naive children and adolescents 6–15 years of age recruited from the Department of Psychiatry at Seoul National University Hospital in Korea and diagnosed with ADHD according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria (American Psychiatric Association 1994). Subjects meeting any of the following criteria were excluded: 1) An intelligence quotient (IQ) score <70; 2) past or current neurological disease; or 3) any evidence of a comorbid psychiatric condition, with the exception of oppositional defiant disorder or anxiety disorder, if medication was not required. We used the Korean Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL) to diagnose ADHD and comorbid disorders (Kim et al. 2004). Intellectual abilities were assessed using the Korean version of the Wechsler Intelligence Scale for Children (KEDI-WISC) (Park and Park 2002).

To compare the genotype frequency of the GRM7 rs3792452 polymorphism, we used data from 159 control group subjects (111 males and 48 females, mean age 9.0±2.7 years) (Park et al. 2013). The subjects were selected for the control group based on the following criteria: 1) Did not meet the criteria for a DSM-IV diagnosis of ADHD according to the Korean version of the Diagnostic Interview Schedule for Children Version-IV (DISC-IV) (Cho et al. 2006); 2) scored below the 90th percentile on the ADHD Rating Scale-IV (ADHD-RS); 3) had a T-score <60 on the Attention Problem subscale of the Child Behavior Checklist (CBCL); and 4) had an IQ score >71 on the KEDI-WISC.

All participants were ethnically Korean. The Institutional Review Board for human subjects at Seoul National University Hospital approved the study, and the parents of the participants provided written informed consent prior to enrollment.

MPH administration and treatment response

Participants took part in a prospective 8 week, open-label study of treatment response to MPH. The subjects underwent clinical assessments prior to treatment. Parents of the children completed the parent version of the ADHD-RS (DuPaul 1991; So et al. 2002), and certified child and adolescent psychiatrists administered the Clinical Global Impressions-Severity (CGI-S) Scale (National Institute of Mental Health 1970; Cunningham et al. 1991; Sung and Cho 1995). Participants were treated with extended-release MPH or osmotic-release oral MPH once per day. The starting dose was determined by a clinical psychiatrist according to participants' body weight and symptoms. Doses of MPH were titrated at weeks 2 and 4 of treatment depending upon symptoms and adverse effects. The maximum dose was 63 mg MPH/day. At each study visit, we asked the parents about medication compliance. Children who skipped medication more than three times throughout the total treatment period were excluded from the study. At the conclusion of the 8 week treatment period, parents were asked to complete the ADHD-RS, and the global improvement of each patient was assessed using the investigator-rated Clinical Global Impressions-Improvement (CGI-I) Scale (National Institute of Mental Health 1970; Cunningham et al. 1991; Sung and Cho 1995). Parents and investigators were blind to the results of the GRM7 genotyping.

We used three methods to assess clinical response to MPH. First, “good responders” were defined as subjects whose ADHD-RS total scores decreased ≥40% from baseline to week 8 of MPH treatment, and the other participants were assigned to the “poor responder” group. Second, subjects with CGI-I scores of 1 (very much improved) or 2 (much improved) after treatment were classified as good responders, whereas those with scores ranging from 3 to 7 were deemed poor responders. Third, the good responder group was defined as subjects showing both a ≥40% decrease in ADHD-RS total scores from baseline and a CGI-I score of 1 or 2 at week 8 of MPH treatment. The other participants were assigned to the poor responder group (Lee et al. 2011).

Genotyping

Genomic DNA was extracted from whole blood lymphocytes using a G-DEXTM II Genomic DNA Extraction Kit (Intron Biotechnology, Seoul, Korea). Detection of an SNP was based on an analysis of primer extension products generated from previously amplified genomic DNA using a chip-based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform (Sequenom, San Diego, CA). Primers in the polymerase chain reaction (PCR) and homogeneous Mass Extend (hME) reaction were designed using Assay Designer 3.1 (Sequenom) (5′-ACG TTG GAT GTG TGA TAC ACA GCT AAG CAG and 5′-ACG TTG GAT GTG AAC CCA AGA CTT CTC ACC for the rs3792452 polymorphism in GRM7).

Statistical analyses

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

Group differences in continuous clinical variables were evaluated using t tests for independent samples. Between-group comparisons of categorical data were assessed using either the χ² test or Fisher's exact test. To investigate the association between the evaluated genotypes and treatment response to MPH, odd ratios (ORs) and 95% confidence intervals were derived from a series of logistic regression analyses using “good response” as the main outcome variable. We used the genotype (G/G or G/A) of the GRM7 rs3792452 polymorphism as the principal predictor after controlling for baseline ADHD-RS score, age, sex, IQ, and final dose of MPH. All statistical analyses were performed using the Statistical Package for the Social Sciences version 21.0 (SPSS Inc., Chicago, IL). The level of significance was set at p=0.05.

Results

Of the 227 subjects initially recruited, 175 (8.8±2.3 years old, male=151, female=24) completed the ADHD-RS and the CGI Scale at the last visit (week 8 of the treatment) and were included in the statistical analysis. Of the DSM-IV ADHD subtypes, the combined type was the most common in our sample (55.4%), followed by the inattentive (32.0%) type. The hyperactive-impulsive and the not-otherwise-specified (NOS) types were identified in 4.0% and 8.26% of the sample, respectively. After 8 weeks of treatment, the mean ADHD-RS score was significantly decreased, from 26.5±10.9 at baseline to 14.2±9.3 (t=14.6, p<0.001), and the mean CGI-I score was 2.6±0.9, indicating a significant improvement in symptoms. Comparisons of initial and final doses of MPH between good and poor responders revealed no significant intergroup differences (see online supplementary Table at http://www.liebertonline.com).

Genotype analysis of the GRM7 rs3792452 polymorphism of subjects with ADHD revealed the G/G genotype in 139 subjects (79.4%) and the G/A genotype in the remaining 36 (20.6%). Genotype analysis of the control group revealed the G/G genotype in 140 subjects (88.1%) and the G/A genotype in the remaining 19 (11.9%). None of the subjects had the A/A genotype. Subjects with ADHD were more likely to have the G/A genotype than were control subjects (χ²=4.50, p=0.034). The genotype distributions of the GRM7 rs3792452 polymorphism were consistent with the expected Hardy–Weinberg equilibrium values in both groups (p>0.05).

Table 1 shows participants' demographic and clinical characteristics according to GRM7 rs3792452 polymorphism genotype. No significant between-group differences were found in age, sex, IQ, frequency of subtype, baseline ADHD-RS or CGI-S scores, or initial or final dose of MPH.

Table 1.

Characteristics of Subjects with ADHD According to GRM7 rsrs37952452 Polymorphism Genotype

	G/G (n=139)	G/A (n=37)	X² or t	p
Sex, male, n (%)	119 (85.6)	32 (88.9)	0.26	0.610
Type, n (%)	69 (48.6)	22 (59.5)	1.91	0.591
Combined	76 (55.1)	20 (55.6)
Inattentive	46 (33.3)	10 (27.8)
Hyperactive–impulsive	6 (4.3)	1 (2.8)
Not otherwise specified	10 (7.2)	5 (13.9)
Age, mean (SD)	8.67 (2.13)	9.33 (2.65)	−1.39	0.171
Intelligence quotient, mean (SD)	107.21 (14.52)	106.14 (13.81)	0.40	0.687
ADHD Rating Scale, mean (SD)	26.34 (11.27)	27.03 (9.56)	−0.34	0.736
CGI-S, mean (SD)	4.50 (0.71)	4.57 (0.78)	−0.49	0.625
Initial dose of MPH (mg), mean (SD)	23.49 (8.32)	23.67 (9.77)	0.08	0.935
Final dose of MPH (mg), mean (SD)	29.41 (11.02)	31.79 (12.53)	−1.02	0.312

GRM7, metabotropic glutamate receptor subtype 7 (mGluR7) gene; ADHD, attention-deficit/ hyperactivity disorder; CGI-S, Clinical Global Impressions-Severity; MPH, methylphenidate.

Table 2 shows the treatment response to MPH according to the GRM7 rs37952452 polymorphism genotype. We found a significant association between the G/A genotype and a good response at the completion of the 8 week treatment period based on ADHD-RS scores (72.2% vs. 55.4%, OR=4.38, p=0.011) after controlling for baseline ADHD-RS score, age, sex, IQ, and final dose of MPH. However, no significant association was found between GRM7 rs37952452 polymorphism genotype and relative frequency of CGI-I 1 or 2 scores posttreatment. When we applied the strictest criteria for treatment response based on the both ADHD-RS and CGI-I scores, subjects with the G/A genotype showed a higher response rate than did those with the G/G genotype (50.0% vs. 35.3%, OR=2.43, p=0.044). Because of the complexity of ADHD-NOS, we conducted the same set of analyses after excluding participants with this condition. Significant associations of the G/A genotype with a good response based on ADHD-RS scores or on both ADHD-RS and CGI-I scores persisted after excluding participants with ADHD-NOS (Table 2).

Table 2.

Methylphenidate Response Measured with the ADHD-RS and/or CGI-I According to GRM7 rsrs37952452 Polymorphism Genotype

	Total sample (n=175)				Sample excluding participants with ADHD-NOS (n=160)
	G/G (n=139) n (%)	G/A (n=36) n (%)	OR (95%CI) ^a	p	G/G (n=128) n (%)	G/A (n=32) n (%)	OR (95%CI) ^a	p
ADHD-RS ≥40% decrease	77 (55.4)	26 (72.2)	4.38 (1.40–13.75)	0.011	75 (58.6)	24 (75.0)	5.14 (1.42–18.67)	0.013
CGI-I ≤2	67 (48.2)	21 (56.8)	1.40 (0.60–3.31)	0.438	64 (49.2)	19 (61.3)	1.58 (0.63–3.95)	0.327
ADHD-RS ≥40% and CGI-I ≤2	49 (35.3)	18 (50.0)	2.43 (1.03–5.77)	0.044	48 (37.5)	17 (54.8)	2.72 (1.08–6.85)	0.034

OR, odds ratios adjusted for age, sex, intelligence quotient, baseline ADHD-RS score, and final dose of methylphenidate.

GRM7, metabotropic glutamate receptor subtype 7 (mGluR7) gene; ADHD-NOS, attention-deficit hyperactivity disorder not otherwise specified; ADHD-RS, Attention-Deficit Hyperactivity Disorder Rating Scale-IV; CGI-I, Clinical Global Impressions-Improvement.

When we compared posttreatment changes in ADHD-RS scores treating the scores as a continuous variable, no significant differences were found between subjects with the G/A genotype and those with the G/G genotype (-13.92±11.91 vs. −11.23±11.28, t=1.27, d=0.23, p=0.205 for the total sample; −15.50±11.51 vs. −11.84±11.48, t=−1.61, d=0.32, p=0.109 excluding participants with ADHD-NOS).

Discussion

We found a significant association between GRM7 rs37952452 polymorphism genotype and treatment response to MPH such that ADHD subjects with the G/A genotype showed a better treatment response than did those with the G/G genotype.

L-glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate receptors are responsible for the majority of excitatory synaptic transmissions and plasticity (Ozawa et al. 1998). Given their central role in neuronal communication and synaptogenesis, glutamate receptors control several cellular and cognitive processes (Riedel et al. 2003). Dysregulated gene expression in the glutamatergic pathway has been reported in spontaneously hypertensive rat models (DasBanerjee et al. 2008; Sagvolden et al. 2009). Furthermore, a neurometabolic study found increased concentrations of glutamate in the brains of subjects with ADHD (Courvoisie et al. 2004).

Although the blocking the dopamine and noradrenaline transporter is the primary mechanism of action of MPH (Leonard et al. 2004; Markowitz et al. 2006), emerging evidence from pharmacological studies indicates that the effect of MPH in ADHD may be partially mediated by the glutamate system. For example, magnetic resonance spectroscopy showed increased glutamatergic tone in the frontal and striatal brain of subjects with ADHD (Jin et al. 2001; MacMaster et al. 2003; Courvoisie et al. 2004), which was normalized by ADHD medication (Carrey et al. 2003). The descending glutamatergic pathways of the prefrontal cortex are thought to be involved in the action of methylphenidate. Glutamate afferents from the prefrontal cortex enhance dopamine cell activity in the ventral tegmental area, and this, in turn, acts synergistically with the psychostimulant-induced increase in dopamine transmission in the nucleus accumbens to promote psychostimulant-induced behavior (Kalivas 2000; Wanchoo et al. 2009).

We found a significant association between the GRM7 genotype and treatment response based on ADHD-RS scores; however, we found no relationship between genotype and CGI-I scores. Because the CGI-S administered by the investigators assessed the global severity of the patient's psychiatric conditions (including combined behavioral problems or social dysfunctions as well as ADHD symptoms per se), the effect of MPH on inattention and hyperactivity may have been reflected in the decreased ADHD-RS scores rather in than the CGI-I scores. Alternatively, it may be that the differences in raters (parents vs. investigators) and the relative sensitivity of the assessment instrument for detecting the drug-induced symptom changes were responsible for this finding.

Limitations

Our study has several limitations that should be considered when interpreting the results. First, because our study was a noncomparative, open-label trial, a genuine placebo effect could not be evaluated. Second, the duration of our MPH treatment period was 8 weeks. A short-term treatment response to MPH may differ from a long-term one. Third, we did not use the investigator- or teacher-rated ADHD-RS to assess the treatment response. Finally, our sample size was small, which may have prevented us from achieving sufficient statistical power to detect significant group differences; therefore, the results should be interpreted cautiously. Further studies, including a replication of our findings in a larger sample and in other populations, are warranted to evaluate the association between glutamate genes and treatment response to MPH in subjects with ADHD.

Clinical Significance

The present study suggests that the GRM7 rs37952452 polymorphism may play a role in the treatment response to MPH in children and adolescents with ADHD such that subjects with the G/A genotype had a better treatment response than did those with with the G/G genotype.

Footnotes

Disclosures

No competing financial interests exist.

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