Atomoxetine: a New Pharmacotherapeutic Approach in the Management of Attention Deficit/Hyperactivity Disorder
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i26 Arch Dis Child: first published as 10.1136/adc.2004.059386 on 21 January 2005. Downloaded from Atomoxetine: a new pharmacotherapeutic approach in the management of attention deficit/hyperactivity disorder J Barton ............................................................................................................................... Arch Dis Child 2005;90(Suppl I):i26–i29. doi: 10.1136/adc.2004.059386 Atomoxetine is a novel, non-stimulant, highly selective lifespan including a potential requirement for lifelong treatment.4 Because of the limitations of noradrenaline reuptake inhibitor that has been studied for existing treatments and the paradigm shift in use in the treatment of attention deficit/hyperactivity thinking about the management of ADHD, there disorder (ADHD). Data from clinical trials show it to be well is an interest in the development of new pharmacological treatments. tolerated and effective in the treatment of ADHD in children, adolescents, and adults. Improvements were seen ATOMOXETINE HYDROCHLORIDE: A not only in core symptoms of ADHD, but also in broader NOVEL TREATMENT FOR ADHD social and family functioning and self esteem. Once-daily Atomoxetine is the first non-stimulant to be approved for the treatment of ADHD and the first dosing of atomoxetine has been shown to be effective in drug to be licensed for the treatment of ADHD in providing continuous symptom relief. Atomoxetine does adults.5 Atomoxetine was licensed in the US in not appear to have abuse potential and is associated with November 2002 and in the UK in May 2004. At the time of writing, it is under consideration for a benign side effect profile. The development of licensing by the regulatory authorities in a atomoxetine thus represents an important advance in the number of other countries. pharmacological management of ADHD. Clinical pharmacology ........................................................................... The neurobiological evidence suggests that drugs that have an effect on dopamine and noradrena- line may have therapeutic potential in ADHD.6 harmacotherapy is an important component Atomoxetine (chemical designation: benzene- of the multimodal management of attention propanamine; (-)-N-methyl-3-phenyl-3-(o-toly- Pdeficit/hyperactivity disorder (ADHD), but loxy)-propylamine hydrochloride; molecular currently this approach is restricted by the formula: C17H21NOHCl) (fig 1) affects the limited range of licensed drugs. Management to regulation of noradrenaline. It is a highly date has been dominated by the use of the selective inhibitor of the presynaptic noradrena- psychostimulants methylphenidate and dexam- line transporter with little or no affinity for other fetamine, for which there is a substantial neurotransmitter transporters and receptors. It http://adc.bmj.com/ 1 evidence base describing their efficacy. increases the availability of extracellular nora- Although the range of formulations of psycho- drenaline in the prefrontal cortex and also stimulants has increased over the years to increases dopamine levels in this region, but include long acting and continuous release not in the nucleus accumbens or the striatum.7 formulations, their use is limited by their This mechanism of action suggests that atomox- duration of action, problematic adverse effects, etine is unlikely to have abuse potential or to abuse potential, and reluctance on the part of 78 cause motor tics. on September 30, 2021 by guest. Protected copyright. some children and families to take controlled Atomoxetine is rapidly absorbed after oral drugs. A range of other drugs including tricyclic administration and can be taken with or without antidepressants, venlafaxine, guanfacine, and food. Peak plasma levels are reached 1–2 hours clonidine are also used in the management of after ingestion. Atomoxetine is metabolised by ADHD; however, the evidence base for their the majority of the general population through effectiveness is less extensive than that for the the cytochrome P450 2D6 pathway, 5–10% psychostimulants and none are licensed for this metabolise it more slowly through a combination purpose.2 of cytochrome P450 and 2D6 enzymes.9 The half The focus of treatment to date has been on the life of atomoxetine is 5.2 hours in rapid meta- relief of the core symptoms of ADHD. However, bolisers and 21.6 hours in slow metabolisers, but there is an increasing awareness of the need to metaboliser status does not affect dose, dose address not only the immediate control of schedule, or side effect profile.10 Atomoxetine is ....................... symptoms, but also broader treatment goals mainly excreted in the urine (80%) with the Correspondence to: encompassing the quality of life of the affected remainder being passed in the faeces. Dr J Barton, North individual and their family. The nature of ADHD Atomoxetine does not appear to induce or inhibit Staffordshire Combined is such that effects can be pervasive, adversely Health Care NHS Trust, the cytochrome P450 2D6 enzyme system, but Moorlands Team, Abbey affecting school, home, and social life. It is other medications that do (for example, parox- Hulton Clinic, Leek Road, associated with adverse outcome in terms of poor etine) increase the availability of atomoxetine.11 Stoke-On-Trent, peer and family relationships and academic In vivo studies indicate that atomoxetine admin- Staffordshire ST2 8BP, UK; underachievement.3 ADHD can persist through istration with substrates of CYP2D6 and CYP3A Joanne.Barton@nsch-tr. wmids.nhs.uk childhood and adolescence into adult life, with does not result in clinically significant drug ....................... implications for affected individuals across their interaction.12 Co-administration of atomoxetine www.archdischild.com Atomoxetine: a new pharmacotherapeutic approach in the management of ADHD i27 Arch Dis Child: first published as 10.1136/adc.2004.059386 on 21 January 2005. Downloaded from versions of the Conners’ questionnaires24 were completed, H3C and here again significant improvements in ADHD total and subscale scores were achieved.13 Whereas a reduction in symptoms is measurable within one week of assignment to atomoxetine, near maximal efficacy is approached by approximately four weeks.13 23 O Atomoxetine demonstrates efficacy comparable to methyl- phenidate in the treatment of ADHD, as established in a 10 10 CH3 week, open label study. Among children with DSM-IV defined ADHD, similar reductions in ADHD symptoms were N seen in both the atomoxetine and methylphenidate treat- H ment groups. Safety and tolerability were also similar for the two drugs. •HCl A six week, randomised, double blind, placebo controlled trial in children confirmed the observation that the duration Figure 1 Structure of atomoxetine. of action of atomoxetine is longer than the five hour blood half life would otherwise indicate, and that once-daily dosing with desipramine, a model compound for drugs metabolised is effective in providing continuous symptom relief.13 The by CYP2D6, did not alter the plasma pharmacokinetics of beneficial effects of atomoxetine were observed until the atomoxetine or desipramine. Similarly, co-administration of evening and settling at bedtime.13 In addition, a study by atomoxetine with midazolam, a model compound for CYP3A Kelsey et al25 showed that once-daily atomoxetine adminis- metabolised drugs, resulted in only a minor statistically tration in the morning was associated with continuous insignificant increase in midazolam plasma exposure.12 symptom relief not only into the evening, but also into the The effects of atomoxetine seem to last longer than would following morning. Dose response in adults was found to be be expected from its pharmacokinetics in that once-daily similar to that in children.17 A recent international study has administration is effective, with behavioural control continu- confirmed the effectiveness of atomoxetine in non-North ing after the drug has apparently been cleared from the American children and young people.26 plasma.13 The reasons for this are not clear, but may be The clinical trials programme has examined in a prelimin- explained by differences in brain and plasma pharmaco- ary way the broader efficacy of atomoxetine with secondary kinetics or by continued effects on the noradrenaline outcome measures addressing effects on comorbidities transporter. including anxiety, depression, and oppositional defiant disorder. Although studies have not been sufficiently Clinical studies powered to provide definitive evidence for efficacy they do The efficacy of atomoxetine in ADHD was first examined in indicate that atomoxetine may have beneficial effects in these 816 adults in a double blind, placebo controlled study, the results areas. Broader social and family functioning has been of which demonstrated its superiority over placebo in assessed in two studies using the Child Health Questionnaire reducing ADHD symptoms and that it was well tolerated.14 (CHQ), a parent rated health outcome scale that measures 8 This was followed by an open label pilot study and a dose physical and psychosocial wellbeing. Michelson et al found ranging study in children and young people, both of which that improvements in social and family functioning and self were positive in demonstrating efficacy and tolerability.15 16 esteem were superior among atomoxetine treated patients http://adc.bmj.com/ An extensive clinical trials programme has been designed compared with those in the placebo group. The 24 hour to investigate the detail of atomoxetine’s