Atomoxetine and stimulants in combination for treatment of attention deficit hyperactivity disorder: four case reports

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 14, Number 1, 2004 Mary Ann Liebert, Inc.
Pp. 129–136 Case Report
Atomoxetine and Stimulants in Combination for Treatment of Attention Deficit Hyperactivity ABSTRACT
Atomoxetine and stimulants have both been demonstrated effective as single agents for treat-
ment of attention deficit hyperactivity disorder in children, adolescents, and adults. How-
ever, attention deficit hyperactivity disorder symptoms in some patients do not respond
adequately to single-agent treatment with these medications, each of which is presumed to
impact dopaminergic and noradrenergic networks by alternative mechanisms in different ra-
tios. Four cases are presented to illustrate how atomoxetine and stimulants can be utilized ef-
fectively in combination to extend duration of symptom relief without intolerable side
effects or to alleviate a wider range of impairing symptoms than either agent alone. This com-
bined pharmacotherapy appears effective for some patients who do not respond adequately
to monotherapy, but because there is virtually no research to establish safety and effective-
ness of such strategies, careful monitoring is needed.
INTRODUCTION
It has shown minimal risk of abuse and is not aschedule II agent; therefore, it can be pre- ATOMOXETINE(ATX), a specific noradrenergic scribed with refills and distributed by physi-
reuptake inhibitor approved by the U.S.
cians in samples. Unlike the stimulants that act primarily on the brain’s dopamine (DA) sys- 2002, is the first new medication approved for tem, ATX exerts its action primarily through treatment of attention deficit hyperactivity the noradrenergic system of the brain.
disorder (ADHD) in many years. In clinical tri- Evidence suggests that there is an important als including 3,264 children and 471 adults (D. Michelson, personal communication, Sep- tember 15, 2003). ATX has been demonstrated (Pliszka 2001). It appears that cognitive man- to be safe and effective as a monotherapy agement systems of the brain can become dys- regulated by either insufficiency of DA and/or is quite different from stimulants, the long- NE in synapses or by excessive synaptic re- established mainstay for treatment of ADHD.
lease of DA and/or NE (Arnsten 2001). There Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
mechanisms of action in agents used to treat and Spencer 1999), but relative importance the disorder, it is likely that ADHD symptoms of these two catecholamines in particular of some patients will respond to one ratio of ADHD subtypes or in particular cases with noradrenergic versus dopaminergic interven- or without specific comorbidities has not been tion better than to another. For many patients, ATX or stimulants are quite effective as single agents for alleviating ADHD symptoms, yet both NE and DA at their respective trans- continue to experience significant problematic porters, the primary mechanism of action of symptoms when treated with either a stimu- these stimulant medications widely used for ADHD is via the dopaminergic system of the In cases where response obtained from a sin- brain (Grace 2001; Pliszka 2001; Solanto et al.
gle agent is insufficient, the possibility of utiliz- 2001). Until ATX the primary noradrenergic ing ATX and stimulants in combination may be medications for treatment of ADHD were the considered. This combined treatment strategy tricyclic antidepressants. These agents have is similar to the combination of MPH with flu- been shown effective for treatment of ADHD, but risks of adverse cardiovascular effects (1993), although that study focused exclusively have caused many clinicians to avoid their use. Analysis of tricyclic antidepressant re- port is concerned with treatment of core symp- sponse profiles suggests that these agents toms of ADHD alone as well as with the more more consistently improve behavioral symp- by various comorbid symptoms (Brown 2000).
measured in neuropsychological testing (Bie- The following case reports describe patients derman and Spencer 1999). In contrast, ATX carefully diagnosed with ADHD who did not has not shown elevated cardiovascular risks respond adequately to treatment with a stimu- and has been shown effective for both inatten- lant or ATX as a single agent. In some cases, tive and hyperactive-impulsive symptoms of ATX was added to an existing regimen of a ADHD (Michelson et al. 2001, 2002, 2003), al- stimulant; in others, a stimulant was added to though relative efficacy of ATX and stimulants a regimen of ATX. Each brief vignette de- scribes the problematic symptoms, the regi- men tried, and the patient’s response. Possible indications for such combined treatment are specific than that of the tricyclic antidepres- described, and risks and benefits to such treat- sants. It inhibits reuptake by the presynaptic NE transporter with minimal affinity forother noradrenergic transporters or receptors(Gehlert et al. 1993; Wong et al. 1982). This pat- ATX ADDED TO STIMULANTS
tern of affinity might suggest that its therapeu-tic benefits derive exclusively from action on noradrenergic circuits, but the process may not response from stimulants for most of their be that simple. Preclinical work by Bymaster et ADHD symptoms or for most of the day, but al. (2002) and Lanau et al. (1997) suggests that not for the full range of impairing symptoms noradrenergic agents such as ATX may act in- directly but potently on the DA system inaddition to their recognized impact on nor- adrenergic receptors. It may be that both stim-ulants and ATX impact both dopaminergic Jimmy, an 8-year-old boy in second grade, and noradrenergic circuits in the brain, albeit type while in kindergarten. He was doing well ATX AND STIMULANTS IN COMBINATION FOR ADHD
throughout the school day on OROS® MPH 27 This case highlights the usefulness of ATX mg q 7 a.m., but this dose wore off by 4 p.m., for alleviating difficulties in falling asleep and leaving the boy restless, irritable, and severely for improving oppositional behavior in late af- oppositional for the ensuing 5 hours until his ternoon, early evening, and morning, times bedtime. During this time Jimmy was unable to focus on homework and often engaged in not yet taken effect. It was not clear whether hostile interactions with playmates and family.
ATX had enhanced positive effects of the MPH He also was very irritable and oppositional during daytime hours, but no negative effects every morning for about an hour until his were reported. The benefits of ATX were ob- tained without the adverse effects that accom- Jimmy had chronic difficulty falling asleep, a panied the trials of MPH-IR administered after Doses of 2.5, 5, and 7.5 mg immediate re- lease MPH (MPH-IR) were tried at 3:30 p.m. tosupplement the morning dose of OROS MPH.
Jennifer, a 17-year-old high school junior had The 2.5- and 5-mg doses were ineffective; the 7.5-mg dose after school was helpful in allevi- inattentive type, in ninth grade. She was treated ating Jimmy’s irritability and oppositional be- initially with Adderall-XR® 20 mg administered havior after school and in the evening. This q 6:30 a.m. as she left for school. Adderall-XR regimen had to be discontinued, however, be- provided coverage only until about 4:30 p.m., cause it left Jimmy with severely diminished which was sufficient for days when homework appetite for afternoon and evening, a serious assignments were relatively light and could be problem for this boy who was underweight.
At the outset of her junior year, Jennifer and chronic difficulty in falling asleep. Clonidine her parents requested medication adjustments 0.1 mg 12 tab q 3:30 p.m. and 1 tab hs was help- that would extend coverage into the evening.
ful in alleviating afternoon irritability and the Because of part-time employment after school, difficulty falling asleep but did not help his Jennifer now had to do her homework in the impaired focus for homework or the serious evening. Also she was now driving herself to problems with morning routine that were very and from school, to and from her job, and to other activities. After she had a minor motor Clonidine was discontinued, and a trial of vehicle accident caused by her being inatten- tive, Jennifer and her parents decided it would the OROS MPH. Jimmy’s sleep problems im- be important for her to have medication cover- proved markedly within a few days. His irri- age in the evening to help her with homework tability and oppositionality improved slightly and to improve her attention when driving.
within a few days and significantly over the Jennifer ’s morning dose was maintained at next 3 weeks after the dose of ATX had been 20 mg of Adderall-XR, and Adderall-IR 10 mg increased to 36 mg at the end of the first week.
was added at 3:30 p.m. This provided cover- In addition, after 3 weeks, parents reported age until about 10 p.m., but it caused Jennifer that Jimmy was generally much less irritable to feel extremely restless and anxious in late afternoon. These adverse effects were not alle- with morning routines, even during the hour viated by reducing the dose of Adderall-IR to 5 before his OROS MPH took effect. Patient has mg. Moreover, the lower dose of IR did not provide enough symptom control for Jennifer men for 4 months with continuing benefit and in the evening for homework, so she had to no adverse effects. Appetite is still somewhat problematic in the evening but much less so than during the treatment with an afternoon started on ATX 18 mg qam for 1 week concur- rent to the existing regimen of Adderall-XR 20 mg qam. After a couple of days of feeling som- enth grade. He was tried on MPH at that time nolent on this combination, she reported no but did not respond well to doses of 10 or 15 other adverse effects and some slight improve- mg tid. When the dose was increased to 20 mg ment in her ability to get homework done in tid, he experienced marked improvement in the evening. ATX was increased to 40 mg qam.
symptoms of both inattention and hyperactiv- She experienced 2 days of somnolence on this ity/impulsivity, but he refused to continue be- increased dose, but this dissipated on the third cause this higher dose caused severe blunting of affect and anorexia. Subsequently he was tried on mixed salts of amphetamine and on feeling calmer, more focused, and more alert OROS MPH. With all of these stimulants, the throughout the day and into the evening until dose required to produce significant allevia- bedtime. For 5 months Jennifer and her par- tion of ADHD symptoms caused the same in- ents have continued to report good control of Frank was then tried on nortriptyline (NT) evening, with no adverse effects reported.
up to 80 mg hs. On this regimen his hyperac- Jennifer was able to tolerate and benefit tive and impulsive symptoms were markedly from the Adderall-XR given in the morning, alleviated, but his inattention symptoms con- but she did not respond well when a second tinued to be problematic, and he disliked the dose of Adderall was given in the afternoon.
regimen because it caused him to feel that he The combination of Adderall-XR with Adder- had lost his “sparkle,” a less severe blunting of all-IR seemed to produce an accumulated level affect than on stimulants, but still uncomfort- by late afternoon that caused her marked rest- able enough to make him reluctant to take the medication. Over 2 years, he had several epi- Adderall-XR with ATX allowed better allevia- sodes of interrupting his treatment with NT to avoid side effects, being frustrated by declin- and into afternoon and evening. On this regi- ing grades and behavior problems, and then men, Jennifer did not feel anxious or restless unhappily resuming treatment on the NT regi- and was able to do well during school, com- plete her homework in the evening, and re- Frank requested a trial of ATX immediately sume her afterschool job. She also reported after it became available. His NT was discon- that she felt more focused when driving in the tinued, and he was started on 25 mg qam for 1 evening, at times when the stimulant would be week, after which the dose was increased to 50 expected to have lost effectiveness. Expanded mg and then, 1 week later, to 80 mg qam. After duration of medication coverage, especially minor gastrointestinal complaints and some for evenings and weekends, for drivers with somnolence in the first week, no adverse ef- fects were reported. Frank initially reported no from elevated safety risks reported for drivers benefit, but after 3 weeks he noticed that he with this disorder (Barkley et al. 2002).
felt more calm throughout the day. His parentsand teachers reported improved behaviorthroughout the day, but they and Frank noted STIMULANTS ADDED TO ATX
that he continued to show much difficulty insustaining concentration for academic tasks.
In week 6, Frank’s regimen of ATX 80 mg response from treatment with ATX alone but qam was divided into 40 mg bid and then aug- continue to suffer with additional impair- ported that this slightly improved his ability toremember what he had read and to focus onhis schoolwork. At his request, the dose was Frank, a 14-year-old ninth grader, had been ATX 40 mg bid. Frank has continued on this diagnosed with ADHD-combined type in sev- regimen for 4 months with no adverse effects.
ATX AND STIMULANTS IN COMBINATION FOR ADHD
He reports that on this regimen he feels “like taining attention to stories, play, or reading ex- my regular self,” and his grades have im- Frank’s intermittent disruption of his treat- for George’s weight had been reached, a trial ment with NT illustrates an important prob- lem that commonly occurs, especially with ATX regimen. This improved George’s behav- adolescent patients. Uncomfortable side ef- ior further and increased his ability to sustain fects such as blunting of affect can signifi- attention in school, but it also caused increased cantly interfere with treatment compliance, difficulty in falling asleep. The ATX dose was even when the regimen significantly improves then split so that George received 18 mg ATX target symptoms. The combination of ATX and with the morning dose of stimulant and 18 mg OROS MPH alleviated this problem that had ATX at dinnertime. This recaptured the im- threatened to totally disrupt Frank’s treat- provement in sleep. George has continued on this regimen for 3 months, with marked im- collaboration with Frank also resulted in better provement at home and school and no adverse control of the wider range symptoms targeted ATX was chosen as an initial intervention for George because it offered the possibility ofaddressing his severe problems in sleep as well as his very problematic oppositional be- havior and inattention using a single agent ADHD-combined type and oppositional defi- with relatively smooth coverage throughout ant disorder after 3 months in full-day kinder- the day. ATX was quite helpful for George, but garten. His teacher complained that George the teacher’s reports of continuing inattention refused to follow directions and was unable to symptoms that were interfering with learning sustain attention to tasks. George’s parents re- highlighted the need for further intervention.
ported that over several years he had been in- A higher dose of ATX was not tried because a creasingly oppositional at home, so much that dose response study of ATX (Michelson et al.
they were unable to get any babysitter to re- 2001) did not show added benefit to doses turn for a second time. He often fought with above 1.2 mg/kg/day. At this point, the com- bination of ATX and stimulant every morning tive and disrespectful to his parents and other was tried. Splitting the dose of ATX provided a adults. Parents also reported that since early way to retain benefits of the stimulant while difficulty in falling asleep. Despite their effortsto calm him, he was unable to settle into sleepuntil 10 to 11:30 p.m.
RISKS OF COMBINING STIMULANTS
George was started on ATX 18 mg qam. Ini- tially he complained of stomachache, but thisdissipated within a few days. Dose was in- Stimulants and ATX have been subjected to creased to 36 mg qam after 1 week. After 2 extensive clinical testing that has demon- strated safety and efficacy in their use as single agents for treatment of ADHD. An enormous evening and was falling asleep without much quantity of research and clinical experience difficulty by 8:30 p.m. They also noted im- has been accumulated with stimulants over the past 30 years. Most of this has been with el- routines and getting off to school. After 3 ementary school children, but there is a sizable weeks, the teacher reported that George was body of research on stimulants with adoles- more cooperative in following directions and cents and with adults as well. Greenhill et al.
had a better attitude with other children but (1999) summarized studies including 5,899 in- noted that he still had much difficulty in sus- dividuals that have shown stimulants to be safe and effective for treatment of ADHD. ATX olism of the ATX. This is evidence to support has not yet been tested for long in the wider the warning from manufacturers of ATX that population of patients treated outside the pro- caution must be used when strong CYP2D6 in- tective restrictions of clinical trials, but it has hibitors such as fluoxetine are used concurrent been demonstrated safe and effective in clini- cal trials involving over 3,700 individuals, a MPH was helpful and well tolerated by this much larger sample than for other nonstimu- patient after the fluoxetine had been fully lant medications tried for ADHD. However, the substantial evidence of safety and effec- Lack of systematic research on use of ADHD agents does not establish satisfactory evidence medications in combination is an example of a of safety and benefits of using these agents broader problem in psychopharmacology, par- ticularly in child and adolescent psychophar- The combination of stimulants with ATX de- macological treatment. The practice of using scribed in these cases has thus far been quite medications in combination is increasingly helpful in alleviating patients’ ADHD symp- widespread. Safer et al. (2003) recently re- toms without any recognized adverse effects.
viewed clinical research and practice literature At present, however, there are virtually no re- from 1996–2002 to assess frequency of con- search data to demonstrate the safety and ef- comitant psychotropics for youths. They re- fectiveness of such combined treatments. The ported that during 1997–1998 almost 25% of manufacturer of ATX has reported that tests of the representative physician office visits for youths in which a stimulant prescription was did not result in increased blood pressure, but written were also associated with use of con- not much more has been published about the comitant psychotropic medication. This was a use of these two medications together.
fivefold increase over the rate in 1993–1994. El- evated rates for use of alternative combina- together, the potential for adverse effects is tions of medications to treat other psychiatric further increased. We had one 18-year-old disorders in children were also found, usually high school student in whom a combination of to treat aggressive behavior, insomnia, tics, three medications produced significant al- depression, or bipolar disorder. Apparently, though transient adverse effects. This stu- combined pharmacotherapy with children is dent’s severe ADHD symptoms and moderate increasing despite the lack of adequate re- dysthymia had responded only partially to 1 search on the safety of such combinations.
year of treatment with OROS MPH 72 mg qam Some might question why clinicians utilize with fluoxetine 20 mg qam. When his continu- ing difficulties with inattention symptoms fore it has been fully evaluated in controlled jeopardized his graduating from high school, trials. Usually the rationale is that apparent ATX 80 mg was added to the existing regimen.
risks for a particular patient appear signifi- After this regimen had been working well for 6 cantly less harmful than the likely risks of not weeks, a taper down was begun to discontinue providing such treatment and that there is po- the fluoxetine. Before the taper down was tential of substantial benefit for a patient suf- completed, the boy reported an acute episode problem with this approach is the dearth of school nurse found his blood pressure to be adequate research to guide estimates of possi- 149/100 mm Hg; previous baseline was con- ble risks and benefits in the use of combined sistently 110/70 mm Hg. All medications were medication treatment. Similar uncertainties discontinued until his pressure was restabi- The cases described in this report reflect var- restarted followed by the OROS MPH a week ious problems that were not life threatening later. The hypertensive episode apparently re- but were significantly impairing the learning, sulted from effects of the fluoxetine on metab- school achievement, family life, and/or social ATX AND STIMULANTS IN COMBINATION FOR ADHD
relationships of these patients in ways that had science. Edited by Solanto MV, Arnsten AFT, substantial negative impact on functioning Castellanos FX. New York, Oxford University and quality of life for the children and their Barkley RA, Murphy KR, DuPaul GI, Bush T: families. Each derived some benefit from treat- Driving in young adults with attention deficit hy- ment with a single agent, but significant peractivity disorder: Knowledge, performance, ADHD symptoms or related impairments per- adverse outcomes, and the role of executive func- sisted on the monotherapy regimen. In these tioning. J Int Neuropsychol Soc 8:655–672, 2002.
cases, neither parents nor clinicians were en- Biederman J, Spencer T: Attention-deficit/hyperac- tivity disorder (ADHD) as a noradrenergic disor- gaged in a quixotic search for perfection; these der. Biol Psychiatry 46:1234–1242, 1999.
children and families were suffering signifi- Brown TE: Emerging understandings of attention cantly from impairing symptoms inadequately deficit disorders and comorbidities. In: Attention alleviated by single-agent treatment.
Deficit Disorders and Comorbidities in Children, In such cases, clinicians need to weigh care- Adolescents and Adults. Edited by Brown TE.
fully potential advantages and risks of accepting Washington (DC), American Psychiatric Press,2000, pp 3–55.
limited benefits obtained from monotherapy Bymaster FP, Katner JS, Nelson DL, Hemrick- versus the potential risks and benefits of utiliz- Luecke SK, Threlkeld PG, Heiligenstein JH, ing combined agents. As Greenhill (2002) ob- Morin SM, Gehlert DR, Perry KW: Atomoxetine served, “The individual practitioner must make increases extracellular levels of norepinephrine key decisions when treating an individual pa- and dopamine in prefrontal cortex of rat: Apotential mechanism for efficacy in attention tient, often without an authoritative answer or deficit/hyperactivity disorder. Neuropsycho- direction from the research literature.” Greenhill added that even when relevant research litera- Gammon GD, Brown TE: Fluoxetine and methyl- ture is available, it yields “averaged group data phenidate in combination for treatment of atten- to evaluate medication effects, possibly missing tion deficit disorder and comorbid depressive important subgroup differences in treatment re- disorder. J Child Adolesc Psychopharmacol 3:1–10, 1993.
sponse” (chapter 9, pp. 19–20). The clinician’s Gehlert DR, Gackenheimer SL, Robinson DW: Lo- task is to tailor treatment interventions utilizing calization of rat brain binding sites for [3H]to- understanding of the relevant science together moxetine, an enantiomerically pure ligand for with sensitive understanding of the particular norepinephrine reuptake sites. Neurosci Lett Grace AA: Psychostimulant actions on dopamine In the four cases presented here, the combi- and limbic system function: Relevance to the nation of ATX with stimulants has apparently pathophysiology and treatment of ADHD. In: been safe and effective. We have obtained sim- Stimulant Drugs and ADHD: Basic and Clinical ilar results thus far in 21 other cases with no Neuroscience. Edited by Solanto MV, Arnsten significant adverse effects. Such anecdotal re- AFT, Castellanos FX. New York, Oxford Univer- ports, however, especially over short time Greenhill L: Stimulant medication treatment of frames, are not sufficient to establish safety. In children with attention deficit hyperactivity dis- the absence of adequate research, decisions to order. In: Attention Deficit Hyperactivity Disor- utilize this combination of ATX and stimulants der: State of the Science, Best Practices. Edited by should be made on a case-by-case basis, with Jensen PS, Cooper JR. Kingston (New Jersey), full disclosure of the limited research base Civic Research Institute, 2002, pp 1–27.
Greenhill L, Halperin JM, Abikoff H: Stimulant given to the patient or parents and with ongo- medications. J Am Acad Child Adolesc Psychia- ing monitoring for effectiveness and possible Lanau F, Zenner M, Civelli O, Hartmann D: Epi- nephrine and norepinephrine act as potent ago-nists at the recombinant human dopamine D4receptor. J Neurochem 68:804–812, 1997.
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