Review article
A review of atomoxetine effects in young people with developmental disabilities

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Highlights

Abstract

This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit.

Conclusions

ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for the emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied.

Introduction

Overactivity and inattention are among the most common behavioral concerns for individuals with developmental disabilities (DD; Emerson, 2003). The prevalence of attention-deficit hyperactivity disorder (ADHD) in this population has been estimated at 9–16% (Emerson, 2003, Strømme and Diseth, 2000), substantially exceeding the rate of ADHD in typically developing (TD) individuals. Stimulants such as methylphenidate are the most extensively studied treatment for ADHD in individuals with DD (Handen & Gilchrist, 2006). Findings indicate that individuals with DD are less likely to show therapeutic benefit and more likely to experience negative side effects from stimulants than are TD individuals (Aman et al., 2008, Handen and Gilchrist, 2006, RUPP, 2005). Thus, there remains a need to identify additional treatment options for this common and impairing set of symptoms in individuals with DD.

Atomoxetine (ATX; Strattera) is a nonstimulant medication of considerable interest. Although ATX only received Food and Drug Administration approval in 2002 for treatment of ADHD, there is a large literature base on effectiveness in TD children, adolescents, and adults (Cheng et al., 2007, King et al., 2006, Kratochvil et al., 2008). Not surprisingly, because of the difficulties in recruiting and testing individuals with DD, the research on any therapeutic agent tends to lag behind that of the TD population. Comparatively speaking, the literature on ATX in people with DD is very small. Moreover, as illustrated by the research on methylphenidate (Research Units on Pediatric Psychopharmacology Autism Treatment Network [RUPP], 2005), medication effects for individuals with DD may differ from effects seen in TD individuals. It is essential that, to the extent possible, clinical decision making is based on findings on the population with DD. We conducted this review in an effort to summarize the available findings in patients with DD and to compare some of these findings relative to TD patients (e.g., data on adverse events [AEs]). Our aims in this paper were to: (a) provide a general context for assessing ATX in individuals with DD by first providing pharmacological data (pharmacodynamics, pharmacokinetics, side effects) from the general/TD population, (b) comment on general advantages and disadvantages of ATX relative to other ADHD medicines, (c) critically review the existing literature on ATX therapeutic effects in DD, (d) characterize the side effects observed in DD samples to determine if they differ from those seen in the TD population, and (e) provide an overall summary and conclusion about the status quo of ATX research in the field of DD. To the best of our knowledge, there is no similar published review to date.

ATX enhances norepinephrine (NE) activity by selectively and potently blocking its reuptake through transporter inhibition and increasing presynaptic concentrations in noradrenergic pathways (Hammerness, McCarthy, Mancuso, Gendron, & Geller, 2009). In the rat, ATX increases NE in regions such as the occipital cortex, lateral hypothalamus, dorsal hippocampus, and cerebellum (Swanson et al., 2006). Increased NE neurotransmission in the prefrontal cortex (PFC) is associated with enhanced attention and higher cognitive processes (Bymaster et al., 2002). ATX increases DA in the PFC because, in contrast to other areas of the brain, DA is taken up by NE transporters in that location. Dopamine is increased in the PFC in animals and is attributed to a common regional uptake inhibition of monoamines (Hammerness et al., 2009; ATX has relatively low affinity for other dopamine and serotonin uptake sites. ATX does not increase the dopamine levels in the nucleus accumbens and associated reward pathways or in the striatum. As a result, it has limited abuse potential and is not associated with tics (Garnock-Jones & Keating, 2009).

Pharmacokinetics are well established in TD children and adults, have been found to be similar after adjusting for body weight, and are linear after 6 years of age, yielding plasma levels predictably proportional to mg/kg dose (Sauer et al., 2005, Witcher et al., 2003). ATX is highly water soluble with high membrane permeability; hence it is rapidly and well absorbed after oral administration. The extent of absorption is unaffected by food, and the manufacturer recommendation is that it may be taken with or without food (Sauer et al., 2005).

Atomoxetine clearance is achieved through three metabolic pathways: aromatic ring- hydroxylation, benzylic hydroxylation and N-demethylation (Hammerness et al., 2009). Primary metabolism occurs via CYP450-2D6, with extensive first-pass liver metabolism via oxidative processes to equipotent primary metabolite 4-hydroxyATX. Further transformation occurs via glucoronidation, resulting in 4-hydroxyATX-O-glucoronide (Sauer et al., 2005). ATX is metabolized to a much lesser degree via CYP2C19 to N-desmethylATX, an active metabolite which exerts minimal pharmacologic activity. Differences in ATX pharmacokinetics are noted between genetically determined CYP2D6 extensive metabolizers (EMs) (over 90% of the population) and CYP2D6 slow metabolizers (SMs) (approximately 7% of population) (Sauer et al., 2005). Plasma clearance of ATX in both EMs and SMs occurs primarily via oxidative pathways, though this occurs at a much slower rate in SMs, yielding higher peak plasma concentrations for the slower metabolizing subgroup (Sauer et al., 2005). Individuals with slow metabolism are at risk for higher serum ATX levels even at lower drug doses, though these pharmacokinetic differences have not been found to be clinically relevant, and dose recommendations are consistent across CYP2D6 genetic subtypes (Sauer et al., 2004), Bioavailability ranges from 63% in EMs and 94% in SMs. Peak plasma levels are typically achieved in 1–2 h in EMs and in 3–4 h in SMs. A high-fat meal reduces the peak plasma concentration, and delays the time it takes to reach peak plasma concentration by 3 h, but does not affect the extent of absorption (Sauer et al., 2005). The volume of distribution into total body water is 0.85 L/kg after an IV dose, and it is well distributed in both EMs and SMs (Sauer et al., 2005). In EMs, twice-daily dosing was not associated with elevated peak plasma concentrations (Witcher et al., 2003). ATX is 98% bound to plasma proteins, primarily to albumin, and does not affect the protein binding of other highly plasma-bound drugs (e.g., warfarin, acetylsalicylic acid, phenytoin, diazepam) to albumin, nor do these drugs affect the protein binding of ATX to albumin (Sauer et al., 2005). Since ATX is highly protein-bound, systemic clearance may be reduced in hepatic insufficiency, and dosage adjustments are advised (Hammerness et al., 2009).

Mean plasma elimination half-lives vary considerably between EMs and SMs. Half-lives of ATX and its metabolites, in EMs, are: (a) ATX, 5.2 h; (b) 4-hydroxyATX, 6–8 h; and (c) N-desmethylATX 6–8 h. Half-lives of ATX and its metabolites in SMs are: (a) ATX, 21 h; (b) 4-hydroxyATX, 19 h and (c) N-desmethylATX 34–40 h. (Sauer et al., 2003). While the primary ATX metabolism is similar in both EMs and SMs, specific metabolite amounts, and rates of formation vary between the subgroups (Sauer et al., 2005).

Excretion of ATX occurs primarily in the urine, with less than 3% of an oral dose excreted unchanged and 80% as 4-hydroxyATX-O-glucoronide; the remaining 17% is excreted in feces (Sauer et al., 2005). ATX does not significantly account for inhibition or induction of metabolism of other CYP-2D6 medications, though drugs that inhibit CYP-2D6, such as paroxetine and fluoxetine, cause slower elimination and increases in peak plasma concentrations (Hammerness et al., 2009).

Clinical trials sponsored by Eli Lilly indicated that serious potential side effects of ATX may include suicidal thoughts, hepatotoxicity, sedation, and weight loss or slowed growth. Common side effects in TD children include upset stomach, decreased appetite, nausea or vomiting, dizziness, tiredness, and mood swings. This was further confirmed by later reviews in the literature Cheng et al. (2007) and Schwartz and Correll (2014). A more detailed review of the literature is reported as follows. Though there was no incidence of completed suicide, the incidence of suicidal ideation was 5/1337 (.0037) compared to 0% taking placebo (Bangs et al., 2008). Patients with DD were not included in the review of Bangs et al. The review did not report incidents of QTc changes or hepatotoxicity. According to Wernicke et al. (2003), ATX caused no QT interval prolongation and minimal changes in diastolic blood pressure in TD children and a minimal increase in pulse rate. Kratochvil et al. (2006) reported a notable change in growth early in treatment, which increased after 18 months indicating that, though there is an early decrease in growth, there was no significant change at 2-year follow-up. Many common side effects reported could be explained as common childhood illnesses (Kratchovil et al., 2006). Wilens, Kratochvil, Newcorn, and Gao (2006) monitored TD children and adolescents and reported that children experienced higher rates of somnolence and headaches than adolescents. There also appears to be a difference in side effects experienced based on titration method. Greenhill, Newcorn, Gao, and Feldman (2007) reported that TD children who were titrated slowly experienced headaches as a common side effect, whereas those who were titrated quickly reported a decrease in appetite and somnolence. This may be pertinent for children with autism spectrum disorder ASD (and perhaps other children with DD) who are notoriously picky eaters. Appetite suppression is often a concern for parents of these children.

Until now, the focus of this paper has been on ATX effects in TD patients; henceforth, we consider individuals with DD (including ASD) as well. Although further research is obviously needed to elucidate the role of ATX in management of ADHD symptoms in the presence of DD, we have enough information for tentative conclusions about its advantages and disadvantages relative to other FDA-approved options. Some of these are based on clinical experience and knowledge of the pharmacological properties of ATX (e.g., pharmacokinetics), whereas others have literature bearing on the issue.

These include the following: (a) ATX may reduce anxiety, an important issue in children with ASD and potentially other DD (Gabriel and Violato, 2011, Dell’Agnello et al., 2009, Ravindran et al., 2009). (This advantage is shared with alpha-2 agonists such as guanfacine.) (b) ATX may have some benefit for depression, although one trial with neurotypical adults was negative (Young, Sarkis, Qiao, & Wietecha, 2011). (c) ATX's longer duration of action provides a smoother effect over time, without the ups and downs of stimulants. (d) Timing of ATX doses is not as critical as with other ADHD medications. (e) ATX appears to have less “rebound irritability” (i.e., disruptive behavior occurring at the end of the day, when the effects of many stimulants wear off) than stimulants. (f) ATX does not interfere with sleep as do stimulants, often important in ASD and other DD (Hollway & Aman, 2011). (g) ATX does not induce or exacerbate tics. (h) There may be less limitation by side effects for ATX than for stimulants if titration proceeds slowly and if doses are split initially. (i) ATX is not a Schedule II drug, allowing refills and phone prescriptions. (j) ATX has little or no abuse potential.

These include the following: (a) ATX takes longer than stimulants to reach an effective level; maximal benefit may be delayed a month or two. (b) The ATX response rate may be lower than for stimulants, at least in TD children. (c) If there are limiting side effects, they may take longer to wash out given the longer half-life of ATX compared with stimulants. (d) Initial split doses to prevent side effects can be inconvenient. (e) Side effects of fatigue or sedation, shared with alpha-2 agonists but not stimulants, can be unacceptable. (f) ATX may pose more gastrointestinal side effects than ADHD alternatives. (g) The risk of reversible liver toxicity exists, although it is rare. (h) ATX may pose sensitivity to metabolic aberrations or enzyme induction or suppression by other drugs. (i) Whereas ATX probably is responsible for less growth inhibition than stimulants, it occurs more frequently than with alpha-2 agonists. (j) In adults, ATX may cause dry mouth, urinary retention, and sexual dysfunction. (k) ATX is irritating to skin and eyes if capsules are opened.

Section snippets

Review method

We used PsychInfo, PubMed, and Google Scholar to search for the following terms in combination with atomoxetine and Strattera: “mental retardation,” “intellectual disability,” “developmental disability,” “autism spectrum disorder,” “autistic disorder,” “autism,” “pervasive developmental disorder,” “PDD,” and “Asperger's disorder.” These searches turned up numerous papers, but the majority simply referred in passing to children with some form of DD and treatment of ADHD symptoms. Ultimately, our

Results

All 11 studies of ATX effects in children with DD are summarized in detail in Table 1. The studies are arranged chronologically and are referenced by numeral (1–11) here. Only two were randomized clinical trials (RCT) with placebo controls; seven were OL prospective, one was an OL retrospective study, and one was a case report. In general, we reference the two RCTs (#2 & 10) in bold font, whereas the remainder are in regular font. In this narrative summary, we focus mainly on primary outcome

Discussion: state of the research in the developmental disabilities

The clinical effects of ATX on ADHD were reportedly positive in all 10 studies that were reviewed, although the effects on co-occurring behavioral and cognitive problems were much less consistent. This positive outcome for ADHD is very welcome, but we note that the large majority of these investigations were not double blind, placebo controlled, randomized clinical trials (RCTs). Thus the effects of publication bias and the extent of placebo response are unknown for much of this work. Our

Summary and conclusions

Our conclusions are as follows. First, ATX holds promise for reducing ADHD symptoms in persons with DD, but only two RCTs have been published at the time of this writing. Second, only one study has been completed in children with ID without ASD, and this was only an open-label study. Clearly, studies are needed to determine the usefulness of ATX in children with ID but without ASD. Third, even in children with ASD, the overall strength of evidence is low. The evidence thus far suggests

Conflict of interest

Dr. Aman has received research contracts, consulted with, or served on advisory boards of Biomarin Pharmaceuticals, Bristol-Myers Squibb, Confluence Pharmaceutica, CogState, Coronado Bioscience, Forest Research, Hoffman LaRoche, Johnson & Johnson, MedAvante Inc., Novartis, Pfizer, ProPhase LLC, and Supernus Pharmaceutica.

Dr. Arnold has received research funding from CureMark, Forest, Lilly, and Shire, advisory board honoraria from Biomarin, Novartis, Noven, Roche, Seaside Therapeutics, and

Acknowledgements

This work was supported by grants from the National Institute of Mental Health to Ohio State University (5R01MH079080), University of Pittsburgh (5R01MH079082-05), and University of Rochester (5R01MH083247).

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