A Current Update on ADHD Pharmacogenomics

Christian Kieling; Júlia P Genro; Mara H Hutz; Luis Augusto Rohde

Pharmacogenomics. 2010;11(3):407-419.

DRD4

The dopamine D4 receptor is considered part of the D2-like receptor family and a G-protein-receptor that has the ability to inhibit the adenyl cyclase enzyme when activated.^[29] The DRD4 gene has been mapped to chromosome 11p15.5,^[30] and is associated with ADHD in both family-based and association studies. The most frequently studied DRD4 polymorphism in ADHD has been the 48-bp VNTR in exon 3. The 7-repeat allele has been proposed as the risk allele, and there is some evidence that this variant is functionally different from 2- and 4-repeat alleles, with the former presenting a blunted response to dopamine in terms of reducing the intracellular concentration of the second messenger cyclic AMP. A recent meta-analysis that included 26 studies indicated a significant, moderate association between ADHD and the 7-repeat allele (95% CIs for odds ratios ranging from 1.15 to 1.54).^[6]

The initial report by Winsberg and Comings found no significant differences in MPH response according to DRD4 genotype (with the 7-repeat allele present among 37.5 and 21.4% of the responders and poor responders, respectively).^[7] Tahir et al. reported an association between DRD4 and MPH response (defined as at least 50% improvement in the number of symptoms) among 29 trios.^[31] There was an excess transmission of the 7-repeat among MPH responders in comparison to nonresponders. In 2001, Seeger et al. examined the association between DRD4 genotype and response to MPH in terms of both physiological response (prolactin levels, whose release is antagonized by MPH dopamine reuptake blocking) and general functioning as estimated by the difference between CGAS 4-week and baseline scores.^[32] The sample composed of 47 inpatients without any psychiatric comorbidities who were treated with MPH monotherapy (0.6–0.8 mg/kg). The authors identified an interaction between the presence of the DRD4 7-repeat allele and the homozygosity for the long alleles of the serotonin transporter gene (5HTT), in which patients with the combination of genotypes showed significantly higher prolactin levels and reduced improvement in CGAS scores.Hamarman et al. studied 45 children aged 7–15 years with ADHD diagnosis and without comorbid conditions.^[33] Individuals received progressively increasing doses of MPH according to symptom remission as measured by serial Conners' Global Index – Parent assessments. Doses were started at 15 mg/day and advanced by 5-mg steps up to symptom normalization or treatment failure (60 mg/day). Children and adolescents with the 7-repeat polymorphism required higher doses of MPH to achieve both initial symptom improvement and complete normalization (mean MPH doses for the 7-present vs 7-absent groups of 30 vs 20 mg and 47 vs 31 mg MPH). Using a dose relative to weight criterion, subjects with the 7-repeat allele required more stimulant medication (1.70 vs 0.79 mg/kg).

Data from the Preschool ADHD Treatment Study showed that participants with the 7-repeat allele exhibited increased social withdrawal with increasing MPH doses, and the 4-repeat DRD4 homozygosity presented an increased risk for picking behaviors with MPH use.^[13] Secondary analyses suggested a trend for an association between another DRD4 polymorphism (located in the promoter region) and teacher composite scores at the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) and Conners, Loney, and Milich (CLAM) scales. Cheon et al. assessed 83 children with ADHD to investigate an association between DRD4 genotype and MPH response.^[34] MPH dosages were increased based on the parents' reports of symptom improvement and side effects, and subsequently maintained for 8 weeks. The authors considered a 'good response' to be the improvement of more than 50% in the ADHD-RS scores after 8 weeks of treatment compared with the baseline ADHD-RS scores before the treatment. They performed a comparison of the response to MPH treatment between subjects with and without the 4-repeat homozygosity at DRD4 and found an increased proportion of 4/4 genotypes among good responders according to both parents and teachers (71.1 and 80.0%, respectively).

Zeni et al., using the methodology described above, did not find statistically significant differences in any outcome measure (symptoms and side effects) according to DRD4 genotype (both 7-repeat presence and 4-repeat homozygosity analyses performed).^[14] No significant response frequencies were also reported by Kereszturi et al., who devised genotype groups according to the presence or absence of the 7-repeat allele.^[17] A similar pattern was found by Tharoor et al. in a retrospective study, where the DRD4 genotype was not associated with MPH response, with 89, 88 and 100% of positive responses for the presence of zero, one and two copies of the 7-repeat allele, respectively (n = 159 for this analysis).^[16] The recent study by McGough et al., using composite measures as outcome, reported a gene–dose interaction between the DRD4 VNTR and the mathematics performance measure, with individuals lacking any copy of the 4-repeat allele worsening in performance at higher doses of MPH.^[21] With respect to the promoter polymorphism, in addition to the link between gene–dose and cognitive performance, there was a significant association with side effects (irritability and somatic symptoms).

Among studies that investigated the role of DRD4 in pharmacological response to MPH among patients with ADHD, the currently available literature still presents conflicting results. In addition to opposite findings, including associations with both the 7-repeat allele and the 4/4 homozygosity, a half of the ten published studies did not find any significant association with clinical response to MPH administration.

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Table 1. Studies assessing the role of the dopamine transporter gene ( *SLC6A3/DAT1*) in clinical response to methylphenidate among individuals with attention deficit hyperactivity disorder.
Study	Study size (n)	Age range (years)	Location	Design	Doses	Outcomes	Improvement definition	Main findings	Ref.
Winsberg and Comings (1999)	30	6–11	USA	Naturalistic	Not < 40 mg/day for nonresponders	ABRS	ABRS scores ≤ 1 in two consecutive assessments	Less improvement for the 10/10 genotype	^[7]
Roman et al. (2002)	50	6–17	Brazil	Naturalistic	Not < 0.3 mg/kg/day for nonresponders	ABRS, CGAS	Reduction of 50% in ABRS, continuous scores for CGAS	Less improvement for the 10/10 genotype	^[8]
Kirley et al. (2003)	119	4–25	Ireland	Retrospective	Not informed	Three-point parental scale and CPRS-R	Categorical rating by parents and continuous scores by CPRS-R	Higher improvement for the 10/10 genotype	^[9]
Cheon et al. (2005)	11	7–12	Korea	Naturalistic	Up to 0.7 mg/kg/day; not < 0.3 mg/kg/day	ADHD-RS	Reduction of 50% in ADHD-RS	Less improvement for the 10/10 genotype	^[25]
Stein et al. (2005)	43	5–16	USA	Clinical trial	18–54 mg/day	ADHD-RS, CGI-I	Reliable change index and cut-off score	Poor response for the 9/9 genotype	^[10]
Van der Meulen et al. (2005)	77	3–18	The Netherlands	Naturalistic	Higher than 0.3 mg/kg/day	SWAN	Continuous: (before–after)/(before)*100	No association with SLC6A3 genotype	^[11]
Langley et al. (2005)	168	6–16	UK	Retrospective	Not informed	CGI-I	'Very improved' or 'very much improved'	No association with SLC6A3 genotype	^[12]
McGough et al. (2006)	81	3–5.5	USA	Clinical trial	Placebo, 1.25, 2.5, 5, 7.5 and 10 mg	SKAMP, CLAM, SERS	Composite SKAMP and CLAM scores	No association with SLC6A3 genotype	^[13]
Mick et al. (2006)	106	19–60	USA	Clinical trial	Initial 0.5 mg/kg/day or 36 mg/day; up to 1.3 mg/kg/day	AISRS; vital signs, adverse effects	Continuous AISRS scores	No association with SLC6A3 genotype	^[22]
Joober et al. (2007)	159	6–12	Canada	Clinical trial	0.5 mg/kg/day	CoGI-P, CoGI-T	Continuous CoGI-P and CoGI-T scores	Poor response for the 9/9 genotype by the CoGI-P	^[15]
Zeni et al. (2007)	106	4–17	Brazil	Naturalistic	Higher than 0.3 mg/kg/day	SNAP-IV, CGAS, SERS	Continuous SNAP, CGAS and SERS scores	No association with SLC6A3 genotype	^[14]
Tharoor et al. (2008)	243	7–19	USA	Retrospective	Not informed	MAGIC-interview	Parent report (yes/no question)	No association with SLC6A3 genotype	^[16]
Kereszturi et al. (2008)	122	Mean 9.6	Hungary	Naturalistic	0.22 to 0.95 mg/kg/day	ADHD-RS; CGI-S	Two-point reduction in CGI-S and 25% reduction in ADHD-RS scores	No association with SLC6A3 genotype	^[17]
Purper-Ouakil et al. (2008)	141	6–18	France	Naturalistic	Flexible; mean: ~30 mg/day	ADHD-RS, CGI-S, TMT, CPT, Stroop test	Primary: ≥ 2 point improvement in CGI-S; secondary: minimum 40% improvement in ADHD-RS	Less improvement for the 10/10 genotype	^[18]
Kooij et al. (2008)	42	20– 56	The Netherlands	Clinical trial	Increasing doses from 0.5 to 1.0 mg/kg/day	ADHD-RS, CGI-ADHD	Two-point reduction in CGI-ADHD and 30% reduction in ADHD-RS scores	Less improvement for the 10/10 genotype	^[23]
Gruber et al. (2009)	177	5–16	Canada and USA	Clinical trial	Montreal: 0.5 mg/kg/day; Washington: 36 mg/day	SERS	Three-factor PCA solution for SERS: emotionality, somatic, over-focused	The 9/10 group had less side-effects than the 9/9 and 10/10 groups	^[19]
McGough et al. (2009)	82	6–17	USA	Clinical trial	Random order of placebo, 5 mg, 10 mg, 15 mg and 20 mg	ADHD-RS, SWAN, PERMP, SERS	Two-factor PCA: ADHD symptoms and correct mathematics in PERMP; four-factor PCA of SERS	No association with SLC6A3 genotype	^[21]

ABRS: Conners Abbreviated Rating Scale; ADHD-RS: ADHD Rating Scale; AISRS: Adult ADHD Investigator System Report Scale; CGAS: Clinical Global Assessment Scale; CGI-I: Clinical Global Impression – Improvement; CGI-S: Clinical Global Impression – Severity; CLAM: Conners, Loney and Milich Scale; CoGI-P: Conners Global Index for parents; CoGI-T: Conners Global Index for teachers; CPRS-R: Conners' Parent Rating Scale – Revised; CPT: Continuous performance test; PCA: Principal Components Analysis; PERMP: Permanent Product Measure of Performance; SERS: Barkley's Stimulants Side Effects Rating Scale; SKAMP: Swanson, Kotkin, Agler, M-Flynn and Pelham Scale; SNAP-IV: Swanson, Nolan and Pelham – IV scale; SWAN: Strengths and Weaknesses of ADHD Symptoms and Normal Behavior; TMT: Trail-making test.

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A Current Update on ADHD Pharmacogenomics

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