Perspectives on Efficacy: An Atomoxetine Tutorial

This article provides answers to several common questions associated with the use of Strattera® (atomoxetine HCl) to treat patients with ADHD. Strattera is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children

age 6 and older, adolescents, and adults.

Is atomoxetine an efficacious medication for ADHD?

There have been more than a dozen double-blind, randomized

controlled ADHD trials of atomoxetine in children, adolescents,

and adults with ADHD and all clinical studies have had a positive

efficacy outcome. Each of these studies demonstrates a very

clear statistically significant and clinically meaningful advantage

of atomoxetine over placebo.

Why do many clinicians report not having the same clinical success with atomoxetine that they might with stimulants or other medications?

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 However, other factors can

also 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. Atomoxetine is a selective

norepinephrine reuptake inhibitor. ADHD symptom reduction

begins early but accrues slowly and steadily over many weeks

before marked benefits are achieved.1 In fact, data suggests that it

may require 4-6 weeks before marked benefits are seen. As a result,

changes in patients are gradual and subtle and therefore can be

more easily overlooked by patients compared to the rapid symptomatic

improvement experienced by some patients taking stimulant

medications every morning. In essence, patients may report that

atomoxetine is not having any effect, when indeed it may be. This

could be because it produces symptom improvement that grows

slowly and steadily over time in contrast to the more apparent daily

onset associated with stimulants.

One possible explanation for a perceived less apparent response

with atomoxetine is that patients who had experienced the more

dramatic response to stimulants previously may be less able to

recognize the more subtle therapeutic benefits of atomoxetine.

What can clinicians do to help patients recognize the therapeutic effects of atomoxetine?

A potential gap in perceived versus actual benefit of atomoxetine

may often be mitigated if clinicians take a more rigorous approach

to evaluating the therapeutic effects of atomoxetine. This means

not relying solely on nebulous, open-ended questions to assess a

patient’s response to the medication (eg, “how are you doing?” or

“do you think the medication is working?”). Given the extremely

subtle course of atomoxetine’s therapeutic effects, patients will,

not infrequently, 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. Prior to

starting treatment, the clinician and patient should create a short

list of frequently occurring and debilitating ADHD target symptoms.

If a treatment is successful, these target symptoms would

decrease noticably. 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 produce

therapeutic benefits even before a patient is aware of it, especially

if they are a patient who has previously experienced the salient,

rapid therapeutic effects of a stimulant.

What are some of the considerations that go intomedication selection?

There is some evidence now that can inform this decision. For

example, a recent double-blind study of children with ADHD and

co-morbid anxiety confirms the experience of many physicians

that atomoxetine may be a good choice in this population, as it

demonstrated significant reduction in ADHD for patients with

ADHD and co-morbid 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 the physician nor the patient

can, a priori, predict which patient will respond well or poorly

to any given 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. I explain to them that the

chronic nature of the illness combined with the general efficacy

of available medications mean that it is likely that they or their

child will be receiving treatment 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, the period they are now in, is the time to

identify the optimal treatment regimen.

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 one of the first-line treatment

options available: one of the long-acting stimulant preparations,

on the one hand, and atomoxetine on the other. This is important

because many patients with ADHD, or parents of children with

ADHD, want a complete resolution of ADHD instantaneously,

and they will gravitate toward a stimulant simply for this reason

when selecting a treatment. This logic can thereby preclude the

opportunity to discover the potential benefits of atomoxetine.

One such benefit is 24-hour symptom coverage; atomoxetine can

provide ADHD coverage beyond the work and school day in a

once-daily dosing regimen. In addition, atomoxetine is the only

FDA-approved, non-scheduled medication for ADHD. With atomoxetine,

clinicians should also be familiar with the safety information

associated with ADHD treatments and share that with their

patients. This would be a discussion about the boxed warning

and other safety considerations. [Please see Important Safety

Information, including Boxed Warning and information regarding

the potential for Strattera to increase suicidal ideation, on page 6

and accompanying Full Prescribing Information on pages 7-13.]

How do patients generally respond to the suggestion of not simply seeking out the most rapid treatment for their ADHD?

My patients respond to this with varying degrees of acceptance.

I would concede that it is frequently the case that an urgent

therapeutic intervention is needed. For example, often by the

time they seek treatment they may be facing severe, imminent

consequences in school. Unless some reason for hope is provided

to teachers or school administrators, “the other shoe is going

to drop”. In those cases, I am usually in agreement with the

parent 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 recently been diagnosed with ADHD for the first time in

their lives. Sometimes they have been struggling with the symptoms

for decades, and 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 often part of ADHD, toward acceptance of a more systematic long-term approach to finding

the optimal treatment regimen. This is important because their

ADHD often impacts not only work but their family, friends, and

social functioning.

Once the context of expectations is set, how do you proceed?

I proceed to explain the risks and benefits of stimulants and

atomoxetine, as well as the potential advantages and disadvantages

of both. I explain that stimulants, while effective

in most patients, have a rapid onset of therapeutic benefit, and

they tend to wear off later in the day. This makes stimulants

a highly timing-dependant treatment; they work for “X”

number of hours a day, “X” being dependent on the specific

formulation of the medications available to treat ADHD and

the patient’s unique metabolism. This requires patients to

be very deliberate about timing in the use of stimulants.11 If

a patient misses a dose after a period of regular compliance,

they may typically experience the re-emergence of the full

effect of ADHD symptoms.

In contrast, atomoxetine takes a lot longer than stimulants

to reach its optimal therapeutic benefit, typically 4-6 weeks,

and sometimes, in my experience, even as long as 8-12 weeks,1

which could be viewed by some patients as a disadvantage.

However, if the patient responds to atomoxetine, he or she may

find convenience with the once-a-day dosing regimen. As with

other medications that are commonly utilized in psychiatry

that have delayed onset of optimal therapeutic benefit, the

therapeutic benefits of atomoxetine do not depend on which

time of day the medication is taken. In fact, it is not uncommon

for patients to take their atomoxetine in the evening or

even right before bedtime, something rarely done by patients

taking stimulants. Therefore, the benefits of atomoxetine are

not limited to “X” hours” after ingestion.2 Similarly, the therapeutic

effects produced by atomoxetine are typically much

more forgiving of missed doses. Patients who miss a dose typically

do not notice any loss of therapeutic benefit right away.3

Thus, the longer time needed for the benefits of atomoxetine

to manifest is often redeemed by the benefit of the 24-hour

ADHD symptom coverage.

Finally, one cannot overlook a difference between stimulants

and atomoxetine. Stimulants, unlike atomoxetine, are

scheduled medications. They are controlled drugs requiring a

special prescription form. For some patients, the requirement

of obtaining a new prescription each time they need more

stimulant medication may be an inconvenience.

Once you have set the appropriate context, educated patients about the chronic nature of treatment, described the main medication options, and discussed safety considerations, what comes next?

At that point I, as all clinicians should do, it is important to take a

thorough medical history and discuss safety considerations in order

to ensure appropriate medication selection. With appropriate screening,

there would be a discussion about important risk information.

One consideration with atomoxetine would be to discuss suicidal

ideation. A more complete summary of safety information can be

found on page 6. I ask them what they think about the medication

options I just described. If they have a strong desire for a medication

that is likely going to work rapidly, they will request a stimulant, at

which point I describe to them the options among the stimulants. If

they are amenable to trying both classes of medications in sequence,

or if they ask my opinion, then I will typically suggest beginning

with a trial of atomoxetine, if this treatment option is right for them.

Patients who have not experienced a stimulant effect may be more

likely to recognize the benefits of atomexetine than those who have

previously experienced a stimulant effect.

If appropriate and the patient agrees to a trial of atomoxetine,

I will initiate therapy, which includes setting appropriate expectations

with patients and titrating to a target dose of 1.2mg/kg

per day for four to six weeks before evaluating full efficacy. It is

important to set appropriate expectations with my patients because,

unlike stimulants, patients on atomoxetine do not have a noticeable

feeling associated with the medication that is common to stimulant

medications, and often do not notice the more gradual onset of atomoxetine.

As result, I will often select and track one or two specific

symptoms that are most troublesome to a patient and then revisit

these symptoms to help gauge the more gradual onset of action

with atomoxetine.