Author(s): Jacob T Brown [*] aff1 , Jeffrey R Bishop aff2
ADHD; atomoxetine; CYP2D6; pharmacogenetics
Atomoxetine was approved in 2002 for the treatment of attention-deficit hyperactivity disorder (ADHD) in adults and children under the brand name Strattera[trademark] [1 ]. As a novel nonstimulant option for the treatment of ADHD, atomoxetine became the third most prescribed ADHD medication in children less than 18 (behind methylphenidate and amphetamine/dextroamphetamine) between 2002 and 2004. The initial surge in utilization was followed by a decline in prescribing between 2004 and 2010 [2 ], despite an increasing prevalence of ADHD. While it is difficult to identify the exact reasons for this decline, it has been suggested that it may have been due to a perceived lack of efficacy among clinicians [ 3 ]. Additionally, prescription rates may have been affected by a Public Health Advisory issued in September of 2005 by the US FDA entitled 'Suicidal Thinking in Children and Adolescents Being Treated with Strattera (Atomoxetine)', although Du et al. note that prescription rates began to decline prior to this [4 ].
Approximately 9% of all children between 6 and 17 years of age in the US have received a diagnosis of ADHD at one point in time [5 ]. Additionally, the overall prevalence of ADHD in children reportedly increased by 33% (from 5.69 to 7.57%) from 1997-1999 to 2006-2008 [ 6 ], while the prevalence in adults is reported to be approximately 4.4% [ 7 ]. Stimulant medications such as methylphenidate and amphetamine/dextroamphetamine are commonly utilized first-line agents for the treatment of ADHD. However, in one 5-year prospective study only half of patients remained on methylphenidate after 1 year, potentially due to tolerability issues related to side effects [8 ]. This, coupled with concerns for abuse/serious adverse events with stimulants, makes a nonstimulant medication such as atomoxetine an attractive alternative treatment option.
Atomoxetine is unique in that it is a nonstimulant therapeutic option for ADHD, with a primary pharmacodynamic mechanism of action involving the selective inhibition of the presynaptic norepinephrine transporter [ 9,10 ]. The onset of action of atomoxetine is somewhat delayed as compared with stimulant medications, possibly due to neuroadaptive changes on noradrenergic receptors following repeated administration [11 ], and typically takes 2-3 weeks for an initial response [12 ]. Although long-term studies reveal that atomoxetine is generally effective in approximately 75% of patients [13 ], extensive metabolism by the highly variable CYP2D6 drug-metabolizing enzyme leads to considerable variability in exposure at standard dosing recommendations. There is variability of CYP2D6 activity observed in different ethnic groups [14 ], and the pharmacokinetic parameters of atomoxetine vary significantly depending upon an individual's CYP2D6 genotype.
While atomoxetine is generally considered safe and tolerable in both poor and extensive metabolizers [15 ], it was included in a 2014 special report on children by the Institute for Safe Medication Practices as the 12th most frequent suspected drug in serious adverse drug events reported in normal medication use between 2008 and 2012 [ 16 ]. Specifically, suicidal ideation and chest pain were the two most...