by David Feifel, MD, PhD
Dr. Feifel is Associate Professor In Residence, Department of Psychiatry; Director, Neuropsychiatry and Behavioral Medicine Program; Director, UCSD Adult ADHD Program, University of California, San Diego Medical Center, San Diego, California.
Funding: The preparation of this column was funded in part by money paid to Dr. Feifel as an advisor to Eli Lilly and Company.
Disclosures: Dr. Feifel has received research funding, consulting, or speaking fees from the following pharmaceutical companies: Abbott Laboratories, AstraZeneca, Argolyn Biosciences, Eli Lilly and Co., Bristol-Myers Squibb, Solvay, Janssen, Wyeth, Macneil, and Shire.
Introduction
In this article Dr. Feifel, addresses some of the common questions associated with the use of atomoxetine (Strattera™) to treat patients with attention deficity hyperactivity disorder (ADHD).
Is atomoxetine an efficacious medication for ADHD?
Dr. Feifel: There have been numerous double-blind, randomized, controlled trials of atomoxotine in children, adolescents, and adults with ADHD, and to my knowledge there has not been a single negative finding; that is each of these studies demonstrates a clear statistically significant and clinically meaningful advantage of atomoxetine over placebo.[1–7] Therefore, it is almost inconceivable that this medication does not have the ability to improve symptoms of ADHD in a meaningful way. However, clinical trial results can only inform us about average effects on large groups of subjects, so it goes without saying that not every person with ADHD is going to experience clinically meaningful benefit from atomoxetine and that has been the clinical experience.
Why do many clinicians report not having the same clinical success with atomoxetine that they might, for example, have with stimulants?
Dr. Feifel: A number of factors may be contributing to the differential perception of efficacy between stimulants and atomoxetine. The most basic explanation is that the magnitude of benefit for many patients may be greater with stimulants and there is some research to support this from head-to-head studies[8,9] comparing atomoxetine to long-acting formulations of stimulant medications. However, in my opinion, other factors typically contribute to the perception of an efficacy gap. Central to these factors, I believe, is the fact that atomoxotine works via a different mechanism of action compared to the stimulants, and therefore, exhibits a different therapeutic time-course. Unlike stimulants, atomoxotine’s ability to ameliorate ADHD symptoms begins early but accrues slowly and steadily over many weeks before the full benefits are achieved.[1] In fact, data suggest that it may require 8 to 12 weeks before full benefits are seen. As a result, changes in patients are subtle and can, therefore, be much more easily overlooked by patients compared to the dramatic, rapid, symptomatic improvement that occurs with stimulants. In essence, patients may report that that atomoxetine is not having any effect, when indeed it may be producing a significant benefit, simply because it produces symptom improvement that grows slowly and steadily over time in contrast to the dramatic daily onset and offset associated with stimulants.
In support of this is a finding from a double-blind, head-to-head study conducted comparing once-daily, long-acting methylphenidate and a daily dose of atomoxetine. A greater percentage of patients reported responding to methylphenidate than to atomoxotine; however, when the data was stratified by previous stimulant use, it is apparent that the majority of patients reporting greater response to methylphenidate were previously treated with stimulants (data on file, Eli Lilly). There was no statistically significant difference between atomoxotine and long-acting methylphenidate among those patients who were stimulant-naive. One interpretation of this result is that patients who had experienced the dramatic benefits of stimulants previously were less able to recognize the more subtle therapeutic benefits of atomoxotine compared to those patients who had not been treated with stimulants.
What can clinicians do to reduce this potential difficulty some patients have recognizing the therapeutic effects of atomoxetine?
Dr. Feifel: This potential gap in perceived versus actual benefit can often be mitigated if clinicians take a more rigorous approach to evaluating atomoxetine’s therapeutic effects. This means not relying solely on nebulous, open-ended questions to assess a patient’s response to the medication, such as, “How are you doing?” or “Do you think the medication is working?” Given the subtle and insidious course of atomoxetine’s therapeutic effects, patients will often answer in the negative to such questions. The clinician must, in those cases, pursue a more meticulous line of questioning aimed at a patient’s specific target symptoms. This means that prior to starting treatment, a clinician should create, in conjunction with his or her patient, a short list of ADHD target symptoms that occur frequently enough and are debilitating enough for that particular patient that if a treatment works its impact would be clearly noticeable on these target symptoms. By doing this, clinicians and patients themselves may be surprised how often an apparent lack of effect by “Gestalt” assessment yields to recognition of improvement upon specific target symptom assessment. Atomoxetine can be having therapeutic benefits even before a patients is aware of it, especially if he or she is a patient who has previously experienced the salient, rapid therapeutic effects of a stimulant.
How does a physician decide which ADHD patient is a good candidate for atomoxetine versus a stimulant?
Dr. Feifel: There is some evidence now that can inform this decision; for example, a recent double-blind study in ADHD children with comorbid anxiety confirms the experience of many physicians that atomoxetine is a good choice in this population as it demonstrated significant reduction in ADHD and anxiety symptoms.10 However, in general, I don’t think we know enough in this regard to reliably categorize patients as optimal candidates for one ADHD medication or the other. The reality is that neither a physician nor a patient can a priori predict who will respond well or poorly to any give medication option. As a result, I take a very different approach, which can be considered the antithesis of trying to match a patient with a medication.
The first priority, and perhaps the most important thing to do in this approach, is to establish the appropriate context and expectations. I educate newly diagnosed adult patients or parents of child patients that ADHD is a chronic condition requiring long-term treatment. The good news, I tell them, is that medications are generally highly efficacious and that there is a strong likelihood that one or more of the available treatments will make a significant positive impact on the patient’s quality of life. The chronic nature of the illness and the general efficacy of the medication taken together, I explain to them, means that it is likely that they or their children will be taking a medication for many years. In my experience, once a medication regimen has been established, patients tend to go on with their lives and do not continually revisit whether the established regimen they are taking is the optimal one. Therefore, I explain to newly diagnosed patients that the initial period after a diagnosis has been made is the time to identify the optimal treatment regimen and it behooves them to invest time to do this. This is important because many ADHD patients or parents want complete resolution of ADHD instantaneously, and will gravitate toward a stimulant simply for this reason, thereby precluding the opportunity to discover the potential unique benefits atomoxetine may hold for them or their children.
During this educational process, I admit to my patients that I cannot reliably predict what medication will be best for them and likewise that they cannot predict this either. As such, I encourage them to consider trying, in sequence, the two most widely divergent, first-line treatment options available: one of the long-acting stimulant preparations and atomoxetine. What I am trying to do is counteract the tendency that patients have to want their ADHD fixed immediately and jump at the most readily available ostensible solution. I’m slowing things down and letting them realize the implications for decisions we make in the first few meetings, which will reverberate for many years down the road.
How do patients generally respond to the suggestion of not seeking out the most rapid treatment for their ADHD?
Dr. Feifel: My patients respond to this with varying degrees of acceptance. Some patients still will insist that they want to be “fixed” immediately, whereas others recognize the logic of what I am advocating and are willing to sign up. With children, I would have to concede that frequently an urgent therapeutic intervention is needed. Often by the time the parents seek treatment, their children are facing severe, imminent consequences from school, unless some reason for hope is provided to teachers or school administrators immediately. In those cases, I am usually in agreement with the parents that a stimulant is the appropriate choice to stabilize the situation. Nevertheless, I still present information about both stimulants and atomoxetine. By laying down the mental ground work, I’ve opened the possibility of revisiting atomoxetine when the situational crisis has settled down.
More perplexing are adult ADHD patients, many of whom have just been diagnosed for the first time in their lives. Even though they have been struggling with the symptoms for decades, they find it hard to tolerate another day of impairment now that the cause is identified. With such patients, I try hard to change the mindset from a perceived need for an immediate, impulsive fix, which is part of the ADHD style, toward acceptance of a more systematic, long-term approach to finding the optimal medication regimen.
Once the context of expectations is set, how do you proceed?
Dr. Feifel: I explain the risks and benefits of stimulants and atomoxetine, as well as the potential advantages and disadvantages of both. Stimulants, I explain have a rapid onset of therapeutic benefit, but also last only as long as they are present in the blood stream. This makes stimulants a highly timing-dependant treatment; they work only for “X” number of hours a day, “X” being dependent on the specific formulation and the patient’s unique metabolism. This requires patients to be very deliberate about the timed use of stimulants. In addition, stimulants do not seem to produce a pervasive benefit beyond their continued use. So if patient misses a dose after three years of regular adherence he or she will typically immediatley experience the re-emergence of full effect of ADHD symptoms.
In contrast, atomoxetine takes longer than stimulants to reach its optimal therapeutic benefit, which is clearly a disadvantage. On the other hand, if the patient responds to atomoxetine, he or she is usually liberated from timing constraints by which stimulant-taking patients must live. Like antidepressants, which also have delayed onsets of optimal therapeutic benefits, precise daily timing of atomoxetine does not seem to be important in regard to the therapeutic benefits of the drug. In fact, it is not uncommon to for patients to take their atomoxetine in the evening or even right before bedtime, something almost unimaginable for stimulants. Therefore, the benefits of atomoxetine are not limited to “X” hours after ingestion.[2] Similarly, the therapeutic effects produced by atomoxetine are typically more forgiving of missed doses. Patients who miss a dose of this medication typically do not notice any loss of therapeutic benefit right away.[3] Thus the longer time needed for the optimal symptomatic benefits of atomoxetine to emerge is returned to patients on the other end, as a longer time to dissipation of its benefits.
Finally, one cannot overlook the important pragmatic differences between stimulants and atomoxetine. Unlike atomoxetine, stimulants are controlled drugs that require special prescription forms and for which physicians cannot call in refills. For some patients, the requirement of obtaining a new prescription each time they need more stimulant medication is a significant logistical burden.
Once you have set the appropriate context, educated patients about the chronic nature of treatment, and described the main medication options, what comes next?
Dr. Feifel: At that point, I put the ball in the patient’s court. I ask my patient what he or she thinks about the medication options I described. A patient who still has a strong desire to be treated with something that is likely going to work rapidly will request a stimulant. In that case, I describe to the patient the options among the stimulants. If the patient is amenable to trying both classes of medications (atomoxetine and a stimulant) in sequence, or if the patient asks my opinion, then I will typically suggest beginning with a trial of atomoxetine, knowing that the optimal patient for a trial of atomoxetine is a patient who has not been exposed previously to stimulants for reasons already discussed.
References
1. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: A randomized, placebo-controlled study. Am J Psychiatry 2002;159(11):1896–901.
2. Kelsey DK, Sumner,CR, Casat CD, et al. Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics 2004;114(1):e1–8
3. Michelson D, Buitelaar JK, Danckaerts M, et al. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: A randomized, double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2004;43(7):896–904.
4. Michelson D, Adler L, Spencer T, et al. tomoxetine in adults with ADHD: Two randomized, placebo-controlled studies. Biologic Psychiatry 2003;53(2):112-20
5. Spencer T, Heiligenstein JH, Biederman J, et al. Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002;63(12):1140–7.
6. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: A randomized, placebo-controlled, dose-response study. Pediatrics 2001:108(5):E83
7. Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155(5):693–5.
8. Kemner JE, Starr HL, Ciccone PE, et al. Outcomes of OROS methylphenidate compared with atomoxetine in children with ADHD: A multicenter, randomized prospective study. Adv Ther 2005;22(5):498–512.
9. Wigal SB, McGough JJ, McCracken JT, et al. A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR) and atomoxetine (Strattera) in school-aged children with attention deficit/hyperactivity disorder. J Attention Dis 2005;9(1):275–89.
10. Lilly Research Laboratories. STR20060106a, STR20060106b. Available at: http://www.strattera.com/hcp/strattera_adhd_anxiety_medication.jsp. Accessed August 1, 2007.
