Enhancement of atomoxetine serum levels by co-administration of paroxetine.

Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in childhood and adolescence. ADHD is characterized by the inability to appropriately modulate attention and/ or impulse control and hyperactivity, resulting in social, academic and occupational underachievement. With a prevalence of 3–5%, ADHD is one of the most frequently seen disorders in child and adolescent psychiatry. Medication represents a major component of a multi-modal treatment plan. Treatment with stimulants is the drug therapy of first choice in ADHD of adulthood. While methylphenidate is mainly used, one third of the patients do not adequately respond to this drug. These patients may profit from a change to treatment with dual active antidepressants. Atomoxetine is a potent and selective inhibitor of the presynaptic norepinephrine transporter that influences not only norepinephrine but also dopamine concentration. It is used for the treatment of ADHD in children, adolescents and adults. The systemic clearance of atomoxetine involves three oxidative metabolic pathways, whereas the aromatic ringhydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is then glucoronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is mediated by cytochrome P450 (CYP), in particular 2D6 (Sauer et al., 2005). Variations in plasma atomoxetine exposures can occur because of genetic variation or as a consequence of co-administration with drugs that inhibit CYP2D6. Very recently Michelson et al. (2007) showed significant differences in serum plasma levels of atomoxetine between CYP2D6 extensive metabolizers (EM) and poor metabolizers (PM). Differences in the CYP2D6 genotype and phenotype as well as pharmacokinetic interventions can potentially affect the clinical profile of atomoxetine as seen in efficacy and tolerability of the drug whereas the effect of potent CYP2D6 inhibition on the pharmacokinetics of atomoxetine has rarely been investigated. Belle et al. (2002) showed that paroxetine markedly affects atomoxetine disposition in healthy individuals, resulting in pharmacokinetics similar to that observed in poor metabolizers of CYP2D6 substrates. Paroxetine is highly metabolized by the liver, resulting in negligible urinary excretion of the intact parent drug (<1%) (DeVane, 2003). Paroxetine undergoes a nonlinear metabolism, steady-state occurs within 8 days and the mean terminal half-life of paroxetine is 18 h which supports a once-daily dosing. The metabolism of paroxetine is largely dependent on the activity of CYP2D6 (Sindrup et al., 1992). The role of paroxetine in clinically significant drug–drug interactions, especially involving metabolic inhibitory effects on the substrates of CYP2D6, has been assessed extensively by a battery of in-vitro studies and clinical pharmacokinetic trials. The recognition of its ability to inhibit CYP2D6 led to a series of studies mostly in healthy volunteers, demonstrating that paroxetine can elevate the plasma concentration of CYP2D6 substrates such as imipramine or desipramine (Alderman et al., 1997; Mitchell, 1997). Despite the demonstration of drug–drug interactions between paroxetine and CYP2D6 substrates in in-vitro studies and in healthy volunteers, there is a marked paucity of reports of clinically significant interactions in psychiatric patients. We therefore report a case of a 38-yr-old patient suffering from adult ADHD, first diagnosed in November 2006, who was then treated with different doses of atomoxetine before paroxetine was added in order to reach higher serum plasma levels of atomoxetine with the expectation of a better clinical outcome concerning symptoms like attention or impulse control.