The adrenergic alpha 2A receptor (ADR2A) is known to be involved in the pathophysiology of attention deficit/hyperactivity disorder (ADHD), especially the symptoms of inattention.
Also, alpha 2A receptor agonists like clonidine and guanfacine are established as treatments for ADHD.
But, do polymorphisms of the gene that codes for the ADR2A receptor predict response to pharmacological treatments for ADHD?
-1291 C>G (or G>C) polymorphism
While other polymorphisms of the ADR2A gene are known, -1291 C>G is the polymorphism that is tested for in one of the commonly available pharmacogenetic test batteries.
As of November 25, 2017, I could find four studies on the association of this specific polymorphism and response to pharmacological treatment of ADHD. Here’s a briefest possible summary of what these studies found:
Study no. 1 (Polanczyk et al., 2007): In one study of children with ADHD, 38% of the children had the C/C genotype. They were compared to those with the G/G or G/C genotypes combined together. The children were treated with methylphenidate for three months, optimized for benefit and adverse effects. Lesser improvement in inattentive symptoms occurred over the first month of treatment in children who had the C/C genotype. The difference was not statistically significantly different after three months of treatment.
But how much was the difference in response? The means SNAP-IV inattentive scores were 2.05 in those with at least one G allele and 1.92 in those with the C/C genotype. The difference in improvement at one month was only 0.3 points and even less than that at 3 months. It wasn’t that those with the C/C genotype did not respond to methylphenidate, they just had a lesser response, especially after one month of treatment.
Study no. 2 (da Silva et al., 2008): A statistically significant association between the polymorphism and response to methylphenidate was found. The percentage of children with a 50% or greater improvement in inattention scores was 73% in those with at least one G allele versus 47% in those with the C/C genotype.
Study no. 3 (Cheon et al., 2009): A good response to treatment with methylphenidate was found in:
77% of children with the G/G genotype
46% of those with the C/G genotype, and
42% of those with the C/C genotype.
Study no. 4 (Contini et al., 2011): In a study of adults with ADHD, no association was found between polymorphisms of the ADR2A gene (including -1291 C>G) and response to methylphenidate.
Since response to treatment of ADHD in children and in adults is not necessarily similar, I would consider the three studies in children differently from those in adults.
Bottomline: This is all we know from the research: In children with ADHD, inattentive symptoms respond better to treatment with methylphenidate over the first month of treatment. and the percentage difference in response is clinically important.
But, we should not wrongly conclude that those with the C/C polymorphism will not respond. It is only that the response in the first month may not be as robust.
We should not generalize these conclusions to adults, other symptoms of ADHD, other treatments, or even treatment beyond the first month.
Clinically, what difference does it make? If we see a child with inattentive symptoms of ADHD who has the C/C genotype, would we not treat with methylphenidate just because the chances of having a good response are somewhat less?
Regarding another possible misinterpretation, I am unaware of any research suggesting that persons with ADHD who have the C/C polymorphism shoud preferentially be treated with alpha-2 agonists.
Bonvicini C, Faraone SV, Scassellati C. Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Mol Psychiatry. 2016 Jul;21(7):872-84. Review. PubMed PMID: 27217152; PubMed Central PMCID: PMC5414093.
Contini V, Rovaris DL, Victor MM, Grevet EH, Rohde LA, Bau CH. Pharmacogenetics of response to methylphenidate in adult patients with Attention-Deficit/Hyperactivity Disorder (ADHD): a systematic review. Eur Neuropsychopharmacol. 2013 Jun;23(6):555-60. Review. PubMed PMID: 22709890.
Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics. 2010 Mar;11(3):407-19. Review. PubMed PMID: 20235795.
Cheon KA, Cho DY, Koo MS, Song DH, Namkoong K. 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 Apr 1;65(7):564-70. PubMed PMID: 19150055.
Contini V, Victor MM, Cerqueira CC, Polina ER, Grevet EH, Salgado CA, Karam RG, Vitola ES, Belmonte-de-Abreu P, Bau CH. Adrenergic α2A receptor gene is not associated with methylphenidate response in adults with ADHD. Eur Arch Psychiatry Clin Neurosci. 2011 Apr;261(3):205-11. PubMed PMID: 21103886.
da Silva TL, Pianca TG, Roman T, Hutz MH, Faraone SV, Schmitz M, Rohde LA. Adrenergic alpha2A receptor gene and response to methylphenidate in attention-deficit/hyperactivity disorder-predominantly inattentive type. J Neural Transm (Vienna). 2008;115(2):341-5. PubMed PMID: 18200436.
Hong SB, Kim JW, Cho SC, Shin MS, Kim BN, Yoo HJ. Dopaminergic and noradrenergic gene polymorphisms and response to methylphenidate in korean children with attention-deficit/hyperactivity disorder: is there an interaction? J Child Adolesc Psychopharmacol. 2012 Oct;22(5):343-52. PubMed PMID: 23083021.
Polanczyk G, Zeni C, Genro JP, Guimarães AP, Roman T, Hutz MH, Rohde LA. 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 Feb;64(2):218-24. PubMed PMID: 17283289.
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