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Atomoxetine,
brand name, Strattera, was approved by the FDA for distribution in November
2002. It became available in US pharmacies in early 2003. Despite its hefty
price tag, it is becoming widely used for adults and children with Attention
Deficit Hyperactivity Disorder. (AD/HD) It is a non-stimulant medication
approved for the treatment of AD/HD in both children and adults. The
stimulants include methylphenidate (Ritalin, Concerta and Metadate CD) and
amphetamine (Dexedrine, Dexedrine Spansules, and Adderall XR). Stimulants are
FDA approved for the treatment of AD/HD in children and adolescents, but most
physicians consider them the first line medication treatment for AD/HD in adults
too.
How Does It Work?
Atomoxetine is a selective
norepinephrine reuptake inhibitor. This means that it strengthens the chemical
signal between those nerves that use norepinephrine to send messages.
Atomoxetine does not appear to affect the dopamine systems as directly as do the
stimulants. Atomoxetine does not seem to cause an increase in brain dopamine
levels in the nucleus accumbens or the striatum areas of the brain. The
stimulants appear to cause an increase in the availability of dopamine in these
areas. The effect on the nucleus accumbens is believed to cause euphoria and to
be responsible for the stimulants’ abuse liability. Dopamine increases in the
striatum may be associated with the risk of motor tics.
(1)
Although Atomoxetine’s direct
effect only seems to be with norepinephrine, it appears to cause a secondary
increase in dopamine levels in the prefrontal cortex area of the brain. (the
brain area behind the eyes.) This part of the brain is associated with the
ability to mentally rehearse responses, and inhibit impulsivity. The area is
also associated with working memory.
Atomoxetine’s chemical
structure bears some similarities to the tricyclic antidepressants although it
is actually a phenylpropanolamine derivative. The tricyclic antidepressants
include desipramine and imipramine. These two medications have been shown to be
effective treatments for AD/HD in adults and children but do not have FDA
approval for this use. The tricyclics affect norepinephrine but are not as
specific as atomoxetine. It is the tricyclics’ effect on neurotransmitters
other than dopamine and norepinephrine that appear to cause their drawbacks.
Their anticholinergic effects can cause constipation, dry mouth and dry eyes.
Their antihistaminergic effects can cause weight gain and tiredness. Their alpha
adrenergic effects can cause tremor and changes in blood pressure.
The tricyclics can cause a delay in cardiac conduction. This effect can cause
minor—and in rare cases—serious changes in heart rhythm. Investigators have
evaluated atomoxetine carefully for cardiac rhythm and blood pressure changes.
Minor, but insignificant, increases in pulse and blood pressure were noted.
Atomoxetine did not appear to cause changes in cardiac conduction. (2)
Can you abuse atomoxetine?
Some
physicians have been reluctant to prescribe stimulants for adults because they
are Schedule II and are officially listed as having a significant potential for
addiction. Although stimulants can indeed be abused, their use does not seem to
cause abuse individuals who do not already have a substance abuse problem.
(3)
However
there are other ways in which stimulants can be abused. Because they decrease
sleepiness and cut appetite, individuals might use them to cram for exams or
lose weight. Atomoxetine appears to have minimal abuse potential. Thus, it is
not as highly controlled as the stimulants. It can inhibit sleep or appetite but
does so much less than the stimulants. Thus, it is less likely to be passed
around.
Does atomoxetine have side effects?
The
side effects of atomoxetine may include many of the side effects seen with
stimulants. These common effects include appetite suppression, sleep
disturbance jitteriness and irritability. Since there is a small increase in
pulse and blood pressure, these should be monitored in patients with cardiac
disease. However, these effects are often milder than those of the stimulants.
However atomoxetine can cause a significant problem with nausea. In my
experience, this is the most common reason for individuals stopping the drug.
Taking it with meals or splitting the dose may help. Atomoxetine is most
commonly given as a single dose in the morning. However there are some
individuals who cannot tolerate this because they actually find the medication
to be sedating. Atomoxetine can lead to urinary retention in some individuals.
It can also cause problems with sexual functioning. About 7 % of men experienced
problems with erections and 3% experienced impotence.
(4) Stimulants often
cause the individual to feel more alert and less sleepy. Atomoxetine can
occasionally do this to a milder degree. In some individuals, however,
Atomoxetine can actually cause sleepiness. I have several patients who prefer to
take it at night. Atomoxetine does not usually have a rebound effect. Although
the compound is metabolized quickly, the clinical effects appear to last all day
and even into the following morning. This can be a good thing for individuals
who find that stimulants make them feel irritable in the evenings. However,
people who need to stimulant “kick” to help them focus may be disappointed in
the new drug.
How Strong and How Fast?
Stimulants start to work in less than an hour. Because of this, one can rapidly
determine the best dose. Atomoxetine has a more subtle, gradual onset. One must
increase the dose over several days or weeks. One may not see the maximum effect
of a given dose for about three weeks. In some cases, I may do a cross over in
which the individual takes a lower dose of the stimulant while waiting for the
atomoxetine to take its full effect. Limited studies have suggested that
atomoxetine is equally effective to methylphenidate (Ritalin) for a variety of
AD/HD symptoms. (2)
In my own experience, this is not always true. Some individuals experience even
the highest recommended doses of the drug as less effective than the
conventional stimulants.
Atomoxetine is metabolized through the cytochrome P-450 2D6 pathway. However
the major metabolite is also active. The activity of the CYP 2D6 system can vary
widely in perfectly healthy people. Individuals who metabolize it slowly will
build up a higher level faster than those who metabolize it rapidly. We often
use blood levels to help us determine the proper dose of a tricyclic
antidepressant. However we do not have such a test widely available for
atomoxetine. Because of this, we may not be able to achieve an effective dose in
some individuals within the FDA dosage guidelines. Fluoxetine (Prozac) and
paroxetine (Paxil),, as well as other drugs affect the metabolism of
atomoxetine. If one is taking atomoxetine it is important to check with the
doctor or pharmacist to make sure that they are not taking any other drugs that
affect its metabolism.
A
Double Edged Sword?
Some
of the advantages of atomoxetine may be a double edged sword. Its lower abuse
potential might make us more willing to prescribe it for individuals with a
substance abuse problem. Its weak antidepressant effect might make us more
comfortable prescribing it for individuals who might have co-morbid depression.
However this should not relieve clinicians from the responsibility for assessing
and treating co-morbid substance abuse and mood problems. Atomoxetine is more
convenient because you can call in refills. However, one of the major reasons
for failure for AD/HD medication treatment failure is inadequate follow up with
infrequent dosage monitoring and adjustments. Medication management visits can
be therapeutic. Frequent visits also help pick up changes in the patient’s
clinical condition.
So, Where Does Atomoxetine Fit In?
I
still recommend the stimulants as the first-line drugs for AD/HD. They have
stood the test of time. We are familiar with their strengths and their side
effects. Their quick onset enables the clinician to more rapidly adjust the
dose. The stimulants—even the newer ones—are less expensive than atomoxetine. I
have found a number of patients who feel that even the higher doses of
atomoxetine are not as effective as the stimulants. However there are many
people who do not respond to stimulants or who cannot tolerate the side effects.
I have achieved excellent results in a number of individuals who felt jumpy or
irritable on stimulants. For these people, atomoxetine can be an excellent
medication.
- Bymaster FP,
Katner JS, Nelson DL, et al.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in
prefrontal cortex of rat: A potential mechanism for efficacy in attention
deficit/hyperactivity disorder. Neuropsychopharmacology 2002;
27:699-711.
- Kratochvil
CJ, Heiligenstein JH, Dittmann R, et al. Atomoxetine and
methylphenidate treatment in children with ADHD: A prospective, randomized,
open-label trial. J Am Acad Child Adolesc Psychiatry 2002;41:776-84.
- Biederman, J, WIlens, T,
Mick, E, Spencer, T, Faraone, SV, Pharmacotherapy of
Attention-Deficit/Hyperactivity Disorder Reduces Risk for Substance Use
Disorder, Pediatrics, 104:2 1999 pe20.
- Michelson D, Adler I,
Spencer T, et al. Atomoxetine in adults with ADHD: two randomized,
placebo-controlled studies. Biol Psychiatry 2003;53:112-20.
Michelson, D, Faries, D, Wernicke, J, Kelsey, D,
Kendrick, K, Sallee, FR, Spencer, T., Atomoxetine in the Treatment of Children
and Adolescents with Attention-Deficit Disorder: A Randomized,
Placebo-Controlled, Dose-Response Study, Pediatrics 2001, 108:5.
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