RISKS OF COMBINING STIMULANTS WITH ATX

Stimulants and ATX have been subjected to extensive clinical testing that has demonstrated safety and efficacy in their use as single agents for treatment of ADHD. An enormous quantity of research and clinical experience has been accumulated with stimulants over the past 30 years. Most of this has been with elementary school children, but there is a sizable body of research on stimulants with adolescents and with adults as well. Greenhill et al. (1999) summarized studies including 5,899 individuals that have shown stimulants to be safe and effective for treatment of ADHD. ATX has not yet been tested for long in the wider population of patients treated outside the protective restrictions of clinical trials, but it has been demonstrated safe and effective in clinical trials involving over 3,700 individuals, a much larger sample than for other nonstimulant medications tried for ADHD. However, the substantial evidence of safety and effectiveness of ATX and stimulants as single agents does not establish satisfactory evidence of safety and benefits of using these agents together.

The combination of stimulants with ATX described in these cases has thus far been quite helpful in alleviating patients' ADHD symptoms without any recognized adverse effects. At present, however, there are virtually no research data to demonstrate the safety and effectiveness of such combined treatments. The manufacturer of ATX has reported that tests of combined administration of MPH and ATX did not result in increased blood pressure, but not much more has been published about the use of these two medications together.

When more than two medications are used together, the potential for adverse effects is further increased. We had one 18-year-old high school student in whom a combination of three medications produced significant although transient adverse effects. This student's severe ADHD symptoms and moderate dysthymia had responded only partially to 1 year of treatment with OROS MPH 72 mg qam with fluoxetine 20 mg qam. When his continuing difficulties with inattention symptoms jeopardized his graduating from high school; ATX 80 mg was added to the existing regimen. After this regimen had been working well for 6 weeks, a taper down was begun to discontinue the fluoxetine. Before the taper down was completed, the boy reported an acute episode of headache and dizziness in school The school nurse found his blood pressure to be 149/100 mm Hg; previous baseline was consistently 110 / 70 mm Hg. All medications were discontinued until his pressure was restabilized for 2 weeks, at which time ATX was restarted followed by the OROS MPH a week later. The hypertensive episode apparently resulted from effects of the fluoxetine on metabolism of the ATX. This is evidence to support the warning from manufacturers of ATX that caution must be used when strong CYP2D6 inhibitors such as fluoxetine are used concurrent to ATX. The combination of ATX and OROS MPH was helpful and well tolerated by this patient after the fluoxetine had been fully washed out, a step that should have been taken prior to adding the ATX.

Lack of systematic research on use of ADHL) medications in combination is an example of a broader problem in psychopharmacology, particularly in child and adolescent psychopharmacological treatment. The practice of using medications in combination is increasingly widespread. Safer et al. (2003) recently reviewed clinical research and practice literature from 1996-2002 to assess frequency of concomitant psychotropics for youths- They reported that during 1997-1998 almost 25% of the representative physician office visits for youths in which a stimulant prescription was written were also associated with use of concomitant psychotropic medication. This was a fivefold increase over the rate in 1993-1994. Elevated rates for use of alternative combinations of medications to treat other psychiatric disorders in children were also found, usually to treat aggressive behaviour, insomnia, tics, depression, or bipolar disorder. Apparently, combined pharmacotherapy with children is increasing despite the lack of adequate research on the safety of such combinations.

Some might question why clinicians utilize a combined pharmacotherapy treatment before it has been fully evaluated in controlled trials. Usually the rationale is that apparent risks for a particular patient appear significantly less harmful than the likely risks of not providing such treatment and that there is potential of substantial benefit for a patient suffering significant impairment. The major problem with this approach is the dearth of adequate research to guide estimates of possible risks and benefits in the use of combined medication treatment. Similar uncertainties exist in many fields of medicine.

The cases described in this report reflect various problems that were not life threatening but were significantly impairing the learning, school achievement, family life, and/or social relationships of these patients in ways that had substantial negative impact on functioning and quality of life for the children and their families. Each derived some benefit from treatment with a single agent, but significant ADHD symptoms or related impairments persisted on the monotherapy regimen- In these cases, neither parents nor clinicians were engaged in a quixotic search for perfection; these children and families were suffering significantly from impairing symptoms inadequately alleviated by single-agent treatment.

In such cases, clinicians need to weigh carefully potential advantages and risks of accepting limited benefits obtained 1mm monotherapy versus the potential risks and benefits of utilizing combined agents. As Greenhill (2002) observed, "The individual practitioner must make key decisions when treating an individual patient, often without an authoritative answer or direction from the research literature." Greenhill added that even when relevant research literature is available, it yields "averaged group data to evaluate medication effects, possibly missing important subgroup differences in treatment response" (chapter 9, pp. 19-20). The clinician's task is to tailor treatment interventions utilizing understanding of the relevant science together with sensitive understanding of the particular patient.

In the four cases presented here; the combination of ATX with stimulants has apparently been safe and effective. We have obtained similar results thus far in 21 other cases with no significant adverse effects. Such anecdotal reports, however, especially over short time frames, are not sufficient to establish safety In~ the absence of adequate research, decisions to utilize this combination of ATX and stimulants should be made on a case-by-case basis, with full disclosure of the limited research base given to the patient or parents and with ongoing monitoring for effectiveness and possible adverse effects.

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REFERENCES

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