Attention-deficit hyperactive disorder (ADHD) is defined as a neurobehavioral disorder characterized by patterns of impulsivity, hyperactivity and inattention affecting development and function. ADHD is now accepted as a genetic disorder, meaning that children and adolescents are genetically predisposed although its genotype—observable characteristics—varies because it too is determined by genetic factors (Froehlich, McGough, & Stein, 2010). Neurobiological studies have mainly focused on how medications impact the catecholamine system (hormones that include norepinephrine, epinephrine and dopamine) and their results indicate that variability of responses to medications are also due to genetic factors (Froehlich, et al., 2010). Hence, understanding of the genetics of ADHD is largely based on the mechanisms involved after introduction of medications and their subsequent responses. As such, clinical studies appear to be focusing on the catecholamine pathways were a variety of genes reside and have been identified as primary candidates for increased risk for ADHD. Science has identified several potential candidates, including dopamine receptors (DRD4 and DRD5), dopa-β-hydroxylase (DBH), dopamine transporter (SLC6A3), synaptosomal-associated protein 25 kDA (SNAP25), serotonin transporter (SLC6A4), and serotonin receptor (HTR1B). Attention is also turning to other suspected genetic culprits, including the noradrenaline transporter protein 1 (SLC6A2), the adrenergic α2A-receptor (ADRA2A), and catechol-O-methyltransferase (COMT; Froehlich, et al., 2010).
As may be surmised by the above, pharmacogenetics is interested medication responses as they relate to genetic variability. As has been mentioned, children and adolescents diagnosed with ADHD carry differing genetic markers, hence the response to medications are also not the same. Pharmacogenetic studies continue to identify these variables—adverse reactions to medications or response failures—in order connect a chain of gene variants impacting enzymes responsible for drug-metabolizing, along with neuro-transporters and -receptors (Froehlich, et al., 2010). Efforts in pharmacogenetics are primarily directed towards effective individualized treatment of ADHD and sustained outcomes. While pharmacogenetics is in its infancy, it is also hoped that by developing efficacious individualized pharmacological approaches there will be less risk of medication side-effects and, thus, increased tolerability; both contributing to long-term well-being and treatment compliance (Froehlich, et al., 2010). Various pharmacogenetic studies are underway which have primarily targeted the influence of candidate genes in the catecholamine pathways to individual responses during treatment studies using methylphenidate (Ritalin, Concentra, etc.). However, more recent studies have taken a fresh approach by looking outside of the catecholamine pathways and have discovered other potential genetic connections that are suspected for their involvement in ADHD.

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It should be noted that Froehlich, et al. (2010) used search terms in their meta-analysis typically used to identify stimulant medications used in the treatment of ADHD and for purposes of pharmacogenetic research. Hence, their findings relate to the use of stimulants such as Ritalin and Concentra. Researchers have studied the effects of methylphenidate and amphetamine on DRD4 and DRD5 and thus far suspect that stimulant medications blocking both may be acting as actuators impacting the underlying pathophysiology of the brain (Froehlich, et al., 2010). In double blind, placebo-controlled trials involving children and adolescents, researchers having differing genotypes who were given oral stimulant medication in order to understand its effect on the region of the brain associated with SLC6A3. Similar naturalistic studies have been conducted that observes children and adolescents in their home and school environments. As of yet, little progress has been recorded using either methodology (Froehlich, et al., 2010). Both studies provide an understanding of the efforts taken by pharmacogenetic research, while the following provide a general sense of further research currently underway. Efforts are looking into genetic variables as they relate to DRD4 dopamine receptors either in controlled or naturalistic settings; others are examining ADRA2A receptors in both animal and human subjects in order to understand how the receptors act as mediators after administering stimulant medication. Efforts appear also to be underway to understand the impact of the various stimulant medications on the metabolic pathways, while others are intent on taking a genome-wide approach, where researchers in pharmacogenomics look at the impact of stimulant medications by studying the human genome (Froehlich, et al., 2010).

While clinical efforts attempting to develop effective treatments for ADHD are quite impressive, there remains a limited array of treatment options. Perhaps the most utilized treatment approach is through psychopharmacology, meaning that stimulant medications such as methylphenidate and amphetamines continues to be the treatment of choice throughout Europe (Huss, Chen, & Ludolph, 2015). While these medications achieve a relatively good response rate, there remains a high number of children and adolescents who do not experience their intended results, for example, by not responding to the drug or experiencing side effects. For these cases, non-stimulant medications may be prescribed. In Europe, noradrenaline inhibitor atomoxetine (ATX) is generally prescribed in such instances, and while their efficacy has been established they also are limited by delayed onset and cardiovascular side effects similar to those of stimulant medications (Huss, et al., 2015). It is also typical in ADHD treatment that a combination approach is taken combining psychostimulant (or non-stimulant) medications with approaches in behavioral therapy.

The latest medication used to treat ADHD is the a2A-adrenergic receptor agonist guanfacine extended release (GXR), which has been approved for patient use in the United States and Europe. GXR is a non-stimulant medication used to support prefrontal cortical cognitive functions, such as memory (Huss, et al., 2015). Developed out of concerns about the impact of ADHD on brain maturation and anomalies to networks and regions involved in cognitive function, GXR is primarily given to patients who cannot take psychostimulant medications. GXR works by stimulating postsynaptic ADRA2A in order to boost noradrenaline within the catecholamine system, and used as a means of countering adrenaline stimulation (Huss, et al., 2015). While researchers don’t fully understand how this interaction may occur, GXR has also been noted to be an antidote to excitatory synaptic inputs by suppressing them. Much of the effects of GXR are reported as hypotheses concerning its efficacy. As such, other researchers have proposed that the counter-balancing effect of GXR may address the impact that ADRA2A has on hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and glutamate transmission, both integral in regulating synaptic inputs (Huss, et al., 2015).

Thus far, the clinical data on the use of GXR shows it to be efficacious when treating ADHD in children and adolescents. It can be used as a standalone medication (monotherapy) or as an adjunct when using psychostimulants (Huss, et al., 2015). Used once-daily, GXR is reported as having reduced core ADHD-related symptoms (inattention, hyperactivity and impulsivity) while also improving cognitive functioning. Compared to other ATX medications, GXR is found to have a faster onset of efficacy and has been proven to be safe and also well tolerated (Huss, et al., 2015). Reported side-effects include: somnolence (drowsiness), fatigue and headaches, and GXR has also been found to effect blood-pressure and heartrate leading to abnormalities concerning blood pressure (hypotension) and heart rate (bradycardia). Various reports concerning ATX and suicide do not appear to be associated with GXR, however there have been reports of patients experiencing hypertension resulting from its discontinuation during treatment (Huss, et al., 2015). As an adjunctive treatment used in Europe, GXR also appears to be effective in the treatment of other conditions such as chronic tic disorders (including Tourette’s), emotional dysregulation, and oppositional defiant disorder. It is surmised that GXR may be efficacious in instances where other psychostimulants cause side-effects, and in juvenile hypertension, other cardiovascular issues, and even in the treatment of substance abuse (Huss, et al., 2015).

    References
  • Froehlich, T. E., McGough, J. J., & Stein, M. A. (2010). Progress and promise of attention-deficit hyperactivity disorder pharmacogenetics. CNS Drugs, 24(2), 99-117. doi:10.2165/11530290
  • Huss, M., Chen, W., & Ludolph, A. G. (2015). Guanfacine extended release: A new pharmacological treatment option in Europe. Clinical Drug Investigation, 36(1), 1-25. doi:10.1007/s40261-015-0336-0