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Atomoxetine for ADHD

Atomoxetine for ADHD

Previous names for atomoxetine were: tomoxetine, LY139603

Brand names: Strattera®; Agakalin®; NIR®; Attencit®; Attentra®; Atteze®; Atastrat®; Concitron®; Strattex®; several generic versions12

1. Mechanism of action

Atomoxetine requires several weeks to build up to its full effect, as is typical with conventional antidepressants. It can take up to 6 months to reach maximum effectiveness.3 According to other sources, atomoxetine begins to take effect within 4 weeks (possibly as early as 1 week in responders). It takes at least 12 weeks to reach full effectiveness.4

It is sometimes reported that depression may occur during the several-week adjustment period with atomoxetine. This likelihood is higher than with methylphenidate, imipramine, nortriptyline (Nortrilen), or bupropion (Elontril).

1.1. Elevated levels of norepinephrine and dopamine in the PFC

In the laboratory, atomoxetine appears to act primarily as a norepinephrine (transporter) reuptake inhibitor. The in vivo results differ from this.5

It should also be noted that the norepinephrine transporter can also reabsorb dopamine, just as the dopamine transporter can also transport norepinephrine.

Atomoxetine

  • increases extracellular norepinephrine in the PFC by a factor of 367
  • increases extracellular dopamine in the PFC by a factor of 3678

Atomoxetine

  • has an extremely high affinity for norepinephrine transporters (NET) for reuptake inhibition (much higher than MPH and AMP) and a much lower affinity for dopamine transporters (DAT) than MPH or AMP. NETs are primarily located in the prefrontal cortex (PFC), whereas DATs are mainly found in the striatum and are responsible for dopamine reuptake.8 The smaller the inhibition constant Ki, the higher the affinity.

  • Atomoxetine (3 mg/kg i.p.) increased the following in rats:9

    • extracellular norepinephrine significantly in
      • PFC
        • Administration of the alpha(2)-adrenergic antagonist idazoxan one hour after atomoxetine further increased norepinephrine release in the PFC. This suggests that adrenergic autoreceptors have an inhibitory effect on norepinephrine release.
        • With chronic administration, the increase in extracellular norepinephrine in the PFC diminished10
      • Occipital cortex
      • Lateral hypothalamus
      • Dorsal hippocampus11
      • Cerebellum
    • extracellular dopamine
      • PFC
      • not in the lateral hypothalamus
      • not in the occipital cortex
      • not in the hippocampus11

In SHR and Wistar-Kyoto rats, atomoxetine increased extracellular dopamine and norepinephrine levels in the PFC.12

Atomoxetine increases the expression of the neuronal activity marker Fos in the PFC by a factor of 3.7.67

Contrary to other assumptions, atomoxetine is therefore not a pure norepinephrine reuptake inhibitor with no effect on dopamine levels.13

The effect of atomoxetine in the PFC explains the improvement in working memory and executive functions.14 A single dose reduces vmPFC activity related to reward evaluation.15
The increase in norepinephrine levels in the PFC caused by atomoxetine is less dose-dependent than with other medications and is therefore more difficult to achieve in a gradual manner.8 A measurement of norepinephrine reuptake inhibition based on the reduction in systolic blood pressure following intravenous injections of tyramine showed that ATX produced significant norepinephrinereuptake inhibition with ATX, which was even more pronounced than that of venlafaxine and began more strongly even at low doses (25 mg/day).16 In contrast, the increase in norepinephrine in the PFC induced by D-amphetamine is significantly more dose-dependent and therefore appears to be much easier to control.8

1.2. No Dopaminergic Effect of Atomoxetine in the Striatum / Nucleus Accumbens

Atomoxetine causes

  • no increase in dopamine in the striatum867
  • and therefore no increase in dopamine in the nucleus accumbens867
  • no increase in the expression of the neuronal activity marker Fos in the striatum or nucleus accumbens
  • No change in the activity of the nucleus accumbens in relation to reward anticipation (as a single dose)15

Therefore, no improvements in hyperactivity/impulsivity and motivation (drive) are to be expected through this mechanism of action. Atomoxetine apparently acts through other mechanisms with regard to hyperactivity and impulsivity.

1.3. Serotonin and Atomoxetine

Atomoxetine also appears to act as a serotonin reuptake inhibitor

  • A study of live monkeys found that atomoxetine affected the serotonin transporter to approximately the same extent as the norepinephrine transporter, meaning that atomoxetine also acted as a serotonin reuptake inhibitor.17
  • Another study also reports that atomoxetine binds to SERT.16 However, the reduction in serotonin levels in whole blood was significantly lower at -40% than that observed with paroxetine or venlafaxine, which was -95%. The improvement in depressive symptoms was comparable to that seen with paroxetine and venlafaxine. The reduction did not depend on the SERT genotype.

Nevertheless, atomoxetine does not alter extracellular serotonin levels

  • in the PFC181210
  • in the striatum10
  • in the hippocampus11

The rare cases of increased suicidal tendencies associated with atomoxetine use are consistent with those seen with SSRIs, suggesting a serotonergic effect.19

1.4. NMDA-glutamate receptor antagonist

Atomoxetine acts as an NMDA glutamate receptor antagonist.20

A study examined the effect of an ATX/D-serine combination on focused attention in rats, which is believed to
is supported by glutamatergic and noradrenergic systems. While low-dose ATX and low-dose D-serine alone had no effect, low-dose ATX and low-dose D-serine together improved attentional performance. D-serine is an NMDA receptor coagonist. The authors concluded that NMDA receptors are involved in the preparatory development of attention and that this process can be facilitated by simultaneously influencing glutamatergic and noradrenergic systems.21
This finding stands in striking contrast to the fact that ATX also acts as an NDMA antagonist.

1.5. Atomoxetine Works Differently Than MPH

Methylphenidate

  • increases extracellular norepinephrine in the PFC (like atomoxetine)6
  • increases extracellular dopamine in the PFC (like atomoxetine)6
  • It is unclear whether MPH also increases extracellular dopamine in the striatum, specifically in the nucleus accumbens (unlike atomoxetine)
    • Increased levels of extracellular dopamine, including in the striatum and, within it, the nucleus accumbens622
      • MPH responders have an increased number of DAT molecules in the striatum, while MPH nonresponders have a decreased number of DAT molecules in the striatum. 23
    • No increase in dopamine levels in the striatum due to MPH24
  • Methylphenidate and atomoxetine increase the efficiency of prefrontal pyramidal neurons, though through different mechanisms:25
    • Methylphenidate reduced nonspecific signals—that is, neural noise—via D1 receptors
    • Atomoxetine increased the strength of specific signals related to the activation of alpha-2 receptors.

The nucleus accumbens is part of the striatum, the brain’s reward/reinforcement system, which is involved in ADHD. Atomoxetine may therefore be beneficial for people with ADHD and acute addiction problems. In cases of impairment of the reward system, methylphenidate and, in some cases, nicotine (patches) are likely to be more effective.

1.6. Specific Mechanism of Action on Hyperactivity/Impulsivity

Hyperactivity and impulsivity can also be caused by overexpression of the ATXN7 gene in the PFC and striatum.26 In this case, atomoxetine was able to resolve the hyperactivity and impulsivity.

Methylphenidate and amphetamine-based medications increase alpha power in the EEG (in rats), whereas atomoxetine and guanfacine do not.27

Like citalopram, atomoxetine is not thought to improve reaction time variability or response inhibition, unlike MPH.28

1.7. Overview of ATX and Neurotransmitters

1.7.1. Binding Affinity of ATX, AMP, and MPH to DAT, NET, and SERT

The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP), and atomoxetine (ATX) bind with varying affinities to the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SERT). This binding inhibits the activity of the respective transporters.29

Binding affinity: higher for smaller numbers (KD = Ki) DAT NET SERT
MPH 34 - 200 339 > 10,000
d-AMP (Vyvanse, Attentin) 34–41 23.3–38.9 3,830–11,000
l-AMP 138 30.1 57,000
ATX 1451–1600 2.6–5 48–77

1.7.2. Effects of ATX, AMP, and MPH on Dopamine and Norepinephrine by Brain Region

The active ingredients methylphenidate (MPH), amphetamine (AMP), and atomoxetine (ATX) affect extracellular dopamine (DA) and norepinephrine (NE) to varying degrees in different regions of the brain. Table modified from Madras,29.

PFC Striatum Nucleus accumbens Occipital cortex Lateral hypothalamus Dorsal hippocampus Cerebellum
MPH DA + NE (+) DA + NE +/- 0 DA + NE +/- 0
AMP DA + NE + DA + NE +/- 0 DA + NE +/- 0
ATX DA + NE + DA +/- 0 NE +/- 0 DA +/- 0 NE +/- 0 DA +/- 0 NE + (rat) DA +/- 0 NE + (rat) DA +/- 0 NE + (rat) DA +/- 0 NE + (rat)

Note: The NET binds dopamine slightly better than norepinephrine, while the DAT binds dopamine much better than norepinephrine.
Nevertheless, atomoxetine increases dopamine levels only in the PFC and not everywhere it binds to NET, suggesting that a specific mechanism of action is at work here.

2. Quality of Impact

2.1. Effect on Symptoms

Based on experiences from the ADHD forum on ADS.org

  • Atomoxetine increases motivation to a lesser extent than stimulants.
  • Atomoxetine is more effective at treating emotional dysregulation than stimulants.

In a randomized, double-blind study involving n = 200 participants who were nonresponders to MPH, lisdexamfetamine was compared with atomoxetine. Lisdexamfetamine performed significantly better than atomoxetine in 2 of 6 categories and in the overall assessment.30

Atomoxetine reduces the total ADHD-RS-IV score by 3.8 points, compared with 8.9 points for guanfacine.31

Atomoxetine helps reduce mind wandering.32

2.2. Responding

In patient forums, some atomoxetine users reported that atomoxetine produced excellent effects only during the first few days—up to a maximum of about 14 days—after which those effects had significantly diminished or disappeared entirely. This pattern could recur following dosage increases, even multiple times.33 We believe we are recognizing a pattern here, which occurs more frequently with medications for ADHD that primarily exert a tonic noradrenergic effect, and we suspect that this suggests that, in ADHD in general and in people with ADHD in particular, the phasic noradrenaline level is more likely to be impaired than the tonic level.
A “phasic” change refers to a short-term (stress- or exertion-induced) change in the level of a neurotransmitter or hormone.
The tonic component is the steady mirror and its typical circadian fluctuations throughout the day.
Phasic behavior is to tonic behavior as waves are to swell.

If the long-term level of norepinephrine is normal, a regular increase in that level causes receptor downregulation—that is, a compensatory adjustment of the receptors toward reduced sensitivity.
As an unverified hypothesis, we are considering whether intermittent dosing (every 2 to 4 days or a 3-day break between doses) might prevent such receptor adaptations. People with ADHD who have experienced such adaptive reactions may wish to discuss this with their doctor. We strongly advise against conducting any experiments without first consulting your doctor!

For information on the effectiveness of individual medications and treatment options, see ⇒ Effect sizes of various ADHD treatment methods.

3. Indications for which atomoxetine is appropriate or inappropriate

3.1. Nonresponsive to Stimulants

According to prevailing medical opinion, atomoxetine is recommended when neither methylphenidate nor amphetamines are effective, which is reportedly the case for 17%34 to 33%35 of people with ADHD. We suggest trying guanfacine first, especially in younger children and in people with ADHD, since guanfacine has a greater average effect size and fewer side effects than atomoxetine.
Approximately 40%36 to 50%37 of people with ADHD who do not respond to MPH are expected to respond to atomoxetine, and approximately 75% of people with ADHD who respond to MPH are also expected to respond to atomoxetine.37

3.2. Emotional Dysregulation

Only the ADHD symptom of impaired inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen), while the impaired inhibition of emotional regulation is caused noradrenergically by the hippocampus.38 Therefore, the former is likely to respond better to dopaminergic treatment, while emotional regulation and affect control are likely to respond better to noradrenergic treatment.
This is consistent with empirical evidence showing that atomoxetine is significantly more effective (and, above all, provides all-day relief) at treating emotional dysregulation than stimulants. However, because atomoxetine lacks dopaminergic effects in the striatum, it produces a lesser increase in motivation than stimulants, which is why combination therapy is often the key to the success of comprehensive ADHD treatment.

3.3. Comorbid Anxiety Disorder

Positive effects of atomoxetine on comorbid anxiety disorders have been reported,39 with one study finding that atomoxetine resulted in a slightly greater improvement in anxiety symptoms than MPH.40

3.4. Comorbid Social Anxiety Disorder

Positive effects of atomoxetine on comorbid social anxiety have been reported.39

3.5. SCT (sluggish cognitive tempo)

In one study, atomoxetine significantly improved 7 out of 9 SCT symptoms as measured by the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT). The improvement in SCT symptoms was completely independent of ADHD symptoms.41

People with SCT are also particularly likely to be MPH nonresponders. In contrast, there is no difference in the MPH response rate between the ADHD-HI and ADHD-I subtypes.42

3.6. Comorbid Depression

Whether atomoxetine is effective in treating depression is a matter of debate. There are arguments against it4344 45 as well as in its favor. In one study, the improvement in depression symptoms was comparable to that seen with paroxetine and venlafaxine.4647
A study found evidence of a benefit from atomoxetine combined with sertraline in patients with the HTTLPR (SERT) s/s genotype compared to sertraline monotherapy.48

When taking SSRIs concurrently, the potential interaction via CYP2D6 should be taken into account (see below).

3.7. Co-occurring Substance Use Disorders: The Preference for ATX Is Debated

While one school of thought favors atomoxetine for patients with comorbid substance use disorder due to its lower risk of abuse, another view sees advantages in stimulants because of their faster onset of action and greater effect size. According to the updated 2018 European consensus on the diagnosis and treatment of ADHD in adults, it is now well established that stimulants do not increase the risk of addiction in ADHD but, in fact, significantly reduce it while being taken.44

3.8. ATX During Pregnancy

A study found no increase in major congenital malformations, heart defects, or limb malformations following exposure to atomoxetine during the first trimester of pregnancy.49
Risk of neurodevelopmental disorders in children remains unchanged with ATX use during pregnancy (Swedish cohort study, n = 861,650 children of n = 572,731 mothers from 2008 to 2017)50
Atomoxetine Does Not Statistically Significantly Alter the Risk of Miscarriage (Meta-analysis, k = 10, n = 16,621,481)51
Risk of birth defects associated with atomoxetine not statistically significantly altered (meta-analysis, k = 10, n = 16,621,481)51

4. Dosage

The initial dosage of atomoxetine is based on body weight. The starting dose is 0.5 mg/kg/day, and after at least 3 days, it is increased to the target dose of 1.2 mg/kg/day.
However, determining the appropriate dose is just as individualized as it is for MPH or AMP. Reports suggesting that blood levels can be used to determine an individualized dose have not been confirmed with the degree of accuracy required for practical therapeutic use.52

To minimize side effects, a slower titration and a waiting period of at least 1 week before increasing the dose are recommended.53
The medication can be taken as a single daily dose in the morning or in two equal doses in the morning and in the late afternoon/early evening. A single evening dose resulted in fewer side effects but also reduced efficacy.4353

The total daily dose for children and adolescents should not exceed 1.8 mg/kg, but should not exceed 100 mg per day.43 The package insert for Strattera (Lily) in the U.S. specifies 1.4 mg/kg/day or 100 mg.53
A meta-analysis reports an increase in the effect of ATX up to a dose of 1.4 mg/kg, after which the effect levels off.54

The following factors that influence the pharmacokinetics of atomoxetine are discussed:52

  • Food
  • Drug interactions
  • CYP2D6 gene variants
  • CYP2C19 gene variants
  • NET gene variants
  • Dopamine β-hydroxylase gene variants

ATX is safe and effective even when used in combination with stimulants.55

A case study describes the treatment of an atomoxetine overdose.56

A study reports on research into the biphasic release of atomoxetine following once-daily administration.57

5. Time Until Effect Takes Effect

The full effect of ATX becomes apparent only after 6 to 8 weeks of treatment or later. Responders typically show some improvement as early as 4 weeks. Once full clinical efficacy is achieved, it appears to remain at a relatively constant level throughout the day.43

In pooled studies, the median time to response—defined as a 25% improvement in ADHD symptoms—was 3.7 weeks. Further improvement in symptoms may occur up to 52 weeks after the start of treatment.55

In our experience, many people with ADHD begin to notice the first effects within the first week.
People with ADHD even took ATX only on certain days and reported that its effects varied from day to day. However, we strongly advise against this, as there is evidence of a risk of depression.

6. Addressing / Responding

“Response” refers to whether the treatment has a demonstrable effect on ADHD symptoms. People with ADHD who do not respond adequately to a medication are called nonresponders. Being a nonresponder does not mean that the medication has no effect, but simply that the effect falls short of the level of symptom improvement defined in the respective study.

6.1. Response Rates

  • In a placebo-controlled study, atomoxetine resulted in significant improvements in approximately 45% of people with ADHD, compared with 58% of responders on Concerta (MPH) and 28% on placebo.58
  • One review cites a response rate of 60% (40% non-responders)53
  • MPH non-responders are expected to respond to atomoxetine
    • Approximately 50% of people with ADHD, and about 75% of those who respond to MPH, are also expected to respond to atomoxetine.37
    • 43% of MPH nonresponders responded to atomoxetine, and 42% of atomoxetine nonresponders responded to Oros-MPH58
  • Adults with ADHD
    • 28.2% responders at Week 24; 65.2% of non-responders had discontinued ATX59 -Responding: Reduction in the total score on the Conners’ Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) by at least 30% and a reduction in the Clinical Global Impressions of ADHD Severity Scale (CGI-S) score to ≤3 at the endpoint
    • 32.9%) of responders at Week 10; 33.2% of non-responders had discontinued ATX59 -Responding: Reduction in the total score on the Conners’ Adult ADHD Rating Scales—Investigator-Rated: Screening Version (CAARS-Inv:SV) by at least 30% and a reduction in the Clinical Global Impressions of ADHD Severity Scale (CGI-S) score to ≤3 at the endpoint

75% of MPH responders are also expected to respond to atomoxetine.37

A study examined the EEG patterns of atomoxetine responders and nonresponders. According to the study, atomoxetine is more effective in individuals who have increased alpha and delta power in the frontal and temporal regions and who, at the same time, show no abnormalities in the beta and theta bands. Atomoxetine non-responders, on the other hand, exhibited reduced absolute power across all EEG frequencies or increased alpha power accompanied by increased beta power. Over the long term, atomoxetine led to a normalization of the elevated alpha and delta values, whereas these remained unchanged in non-responders. Atomoxetine appeared unsuitable in cases where alpha, beta, and theta values were all elevated simultaneously.60

Neither age, gender, prior use of stimulants, ADHD subtype, CAARS-Inv:SV, nor CGI-S were statistically significant predictors of response to ATX. Reductions in the CAARS-Inv:SV total score, the CAARS-Inv:SV subscores, and the CGI-S at week 4 in the short-term analysis and at week 4 or 10 in the long-term analysis were statistically significant predictors of response.59

6.2. Therapeutic Reference Range, Reference Blood Levels

The therapeutic reference range (Cmax ranges for therapeutically effective doses) for atomoxetine was reported as follows:61

  • 200–1,000 ng/mL, 60 to 90 minutes after taking 1.2 (mg/kg) per day

Half-life: 2 to 5 hours61, 3.11 hours (10 mg)62
Laboratory value warning threshold: 2000 ng/ml

Maximum serum levels after two hours (10 mg orally)62

The specified therapeutic reference range is a population-based statistical value that cannot be applied directly to individual patients. Optimal neuropsychopharmacotherapy would therefore require determining the individual’s optimal therapeutic concentration range on a case-by-case basis. To do this, for example, blood levels can be measured after improvement has occurred.61

7. Side Effects of Atomoxetine

7.1. Atomoxetine and Cardiovascular Problems

When starting treatment with atomoxetine, patients should be monitored for cardiac arrhythmias during the first week. In a self-controlled case series involving 15,472 individuals starting atomoxetine and 12,059 starting methylphenidate, an increased risk of cardiac arrhythmias was observed in the first 7 days after the first dose of atomoxetine (adjusted incidence ratio 6.22; 95% CI 1.90 to 20.35) and upon re-exposure (3.23; 95% CI 1.58 to 6.64). There was no association between MPH and cardiac arrhythmias, nor between either active ingredient and heart failure.63 The confidence interval of 1.90 to 20.35 is very wide.

On average, atomoxetine causes a 6.4-beat increase in heart rate, Concerta (MPH) a 3-beat increase, and the placebo a 0.3-beat increase.64

Systolic blood pressure increased on average:64

  • for atomoxetine, by 3.7
  • for Concerta (MPH), by 2.4
  • by 1.3 for the placebo

Diastolic blood pressure increased on average:64

  • for atomoxetine, by 3.8
  • for Concerta (MPH), by 3.1
  • by 0.4 for the placebo.

A large study involving n = 2,566,995 children found no increased risk of serious cardiovascular events—such as stroke, heart attack, or cardiac arrhythmias—associated with atomoxetine.65
One study found an increased risk of cardiac arrhythmias during the first 7 days following initial exposure to atomoxetine (aIRR 6.22) and during subsequent exposure (aIRR 3.23). In contrast, no increased risk of cardiac arrhythmias was found with methylphenidate.66

A 14-year study found a 4% increase in the risk of cardiovascular problems for each year of use of stimulants (methylphenidate, amphetamine-based medications) and, to a slightly lesser extent, the non-stimulant atomoxetine.67

A study found no prolongation of the QTcF or QTcB to more than 500 ms or an increase of more than 60 ms.68

7.2. Atomoxetine increases histamine levels

ATX increases histamine levels,6970 just like all other known ADHD medications:

  • Amphetamine-based medications
  • Methylphenidate
  • Modafinil
  • Nicotine
  • Caffeine

As a result, people with histamine intolerance often experience problems when taking ADHD medications.
A person with ADHD and histamine intolerance reported that she could not tolerate AMP or sustained-release MPH at all, but was able to tolerate immediate-release MPH in small doses.

7.3. Other Side Effects of Atomoxetine

Atomoxetine resulted in a weight loss of 0.6, Concerta (MPH) in 0.9, and the placebo in 1.1 (i.e., a greater weight loss than with ATX and MPH).64
Atomoxetine has been associated with a low rate of elevated serum aminotransferase levels and with rare cases of acute, clinically evident liver damage.71
Long-term use of atomoxetine for more than 3 years increased the risk of type 2 diabetes by 44%.72 Methylphenidate reduced the risk during the first few years of use, and lisdexamfetamine had no effect.

Studies found the following side effects of atomoxetine (as a percentage of people with ADHD):

  • Loss of appetite 14.9%73
  • Insomnia: 11.3%73
  • erectile dysfunction: 8.0% vs. 1.9% with placebo74
  • Urinary retention: 6.9% vs. 2.4% with placebo74
  • Drowsiness: 6.0%73
  • decreased libido: 4.6% compared with 3.0% in the placebo group74
  • Dysuria: 3.7% vs. 1.5% with placebo74
  • Ejaculation disorders: 2.8% vs. 1.1% with placebo74
  • reduced urine flow: 2.5% vs. 0.6% with placebo74

Sexual and urological disorders are associated with a possible nonselective peripheral effect on the adrenergic nerve endings in the smooth muscle cells of the sphincter and the urethral arteries.75 Atomoxetine improved nocturnal enuresis in children.76

A warning is issued regarding the (rare) possibility77

  • serotonin syndrome
  • highly aggressive behavior

The studies do not allow us to conclude whether the increase in the prevalence of psychosis is due to the presence of ADHD or to the use of stimulants.

A 21-year-old man developed serotonin syndrome—characterized by profuse sweating, marked agitation, drowsiness, mild fever, palpitations, a prolonged QT interval, muscle twitching, tremors, and heightened reflexes. After administration of activated charcoal and a generous infusion, the symptoms resolved within three days.78

Another study found an 8-fold increased risk among people with ADHD who were taking ADHD medication (0.34% vs. 0.048%).79 Since this study compares people with ADHD who are taking medication—rather than people with ADHD and no medication—to the general population, no reliable conclusions can be drawn about the role of ADHD medications. The absolute risk of a first-time episode of psychosis or mania upon starting medication was dependent on the active ingredient:

  • Atomoxetine: 0.60% (highest)
  • Amphetamine-based medications: 0.33%
  • Methylphenidate: 0.19%

At therapeutic doses of up to 1.2 mg/kg, atomoxetine was not genotoxic. At doses of 6 mg/kg or higher (5 times the therapeutic dose), atomoxetine began to exhibit genotoxic effects.80

7.3. Contraindications for Atomoxetine

Contraindications include

  • taking MAO inhibitors within the last 14 days
  • Narrow-angle glaucoma
  • severe heart and vascular diseases that may worsen with even a slight increase in blood pressure or heart rate

Atomoxetine carries a warning about an increased risk of suicidal thoughts in children and adolescents.
However, a large meta-analysis found that the observed increases in the risk of suicidal thoughts or attempts, depression, or aggression associated with atomoxetine were not statistically significant.81

8. Metabolism of Atomoxetine

8.1. Elimination via normal CYP2D6 metabolism

The primary route of metabolism for atomoxetine (98.4%)82 occurs in the liver via the enzyme CYP2D6 (cytochrome P450 2D6), resulting in 4’-hydroxyatomoxetine, which is just as effective as atomoxetine itself. In addition to CYP2D6 (which metabolizes ATX 475 times faster than the other enzymes)83, CYP2C19, CYP3A, CYP1A2, CYP2A6, and CYP2E1 are involved in the metabolism to 4’-hydroxyatomoxetine.84

4’-Hydroxyatomoxetine is glucuronidated to form the inactive 4’-hydroxyatomoxetine-O-glucuronide.85

A minor metabolic pathway accounting for 1.5% of82 is N-desmethylation. This is primarily mediated by CYP2C19.83

Another degradation pathway is benzyl oxidation.84

8.2. Elimination with Reduced CYP2D6 Metabolism

About 5 to 7% of people have a genetic polymorphism that makes them poor metabolizers. In slow metabolizers, the half-life increases to about 21.6 hours. 86
In individuals with moderate or poor CYP2D6 metabolism, ATX can also be converted (in vitro) by CYP2E1 and CYP3A to 4’-hydroxyatomoxetine. In the poorest metabolizers, biotransformation by CYP2B6 to 2-hydroxymethylatomoxetine (2-CH₂OH-ATX) predominates.87 Nevertheless, the total clearance of ATX remained impaired in poor CYP2D6 metabolizers.
In patients with extensive CYP2D6 metabolism, the majority of ATX was excreted within 24 hours; in patients with poor CYP2D6 metabolism, it was excreted within 72 hours.88

In children, the metabolism of ATX by CYP2D6 is impaired. In vitro, the production of alternative metabolites (N-desmethylatomoxetine and 2-hydroxymethylatomoxetine) has been observed.88 This conflicts with studies that observed an age-dependent impairment of CYP2D6 metabolism only during the first one or two weeks of life.87

The efficacy of CYP2D6 metabolism is influenced by genetic variants of the POR gene (cytochrome P450 oxidoreductase).89

For more information, see CYP2D6 Metabolizing Enzyme and Effects and Duration of Action of ADHD Medications.

8.2. Clearance with Increased CYP2D6 Metabolism

A small number of people are ultra-rapid metabolizers. For ultra-rapid metabolizers, the half-life is about 5 hours.86

9. Interactions

9.1. Atomoxetine and CYP2D6

The metabolism of atomoxetine by CYP2D6 depends on genetic factors, which complicates dosing. A study describes the prediction of atomoxetine plasma levels using simple, physiology-based pharmacokinetic models.9091

9.1.1. In people with ADHD and genetically reduced CYP2D6 metabolism

9.1.1.1. Atomoxetine without CYP2D6 inhibitors

In patients with poor CYP2D6 metabolism, the average blood level of atomoxetine was 10 times higher than in patients with extensive CYP2D6 metabolism.
High response rate to atomoxetine (80% according to the manufacturer), accompanied by increased side effects, which, however, do not usually lead to discontinuation of the medication. It is recommended to start with a low dose (40 mg/day).92
We are aware of cases of side effects associated with dose titration that were significantly reduced by a slow titration process (8 mg/day increments, increased every 4 days).

9.1.1.2. Atomoxetine when taken concurrently with CYP2D6 inhibitors

In patients with poor CYP2D6 metabolism, additional administration of CYP2D6 inhibitors did not further increase the atomoxetine blood levels, which were already 10 times higher than normal, since people with genetically determined poor CYP2D6 metabolism do not, in fact, undergo CYP2D6 metabolism.92

9.1.2. In people with ADHD and genetically enhanced CYP2D6 metabolism

9.1.2.1. Atomoxetine without CYP2D6 inhibitors

In cases of extensive CYP2D6 metabolism without concomitant use of CYP2D6 inhibitors, average atomoxetine blood levels were lower compared to cases of extensive CYP2D6 metabolism (peak plasma concentration below 200 ng/mL 1–2 hours after administration). Low response to atomoxetine (60% according to the manufacturer). A dose increase may be necessary, possibly up to or exceeding 100 mg/day in adults.92

9.1.2.2. Atomoxetine when taken concurrently with CYP2D6 inhibitors

In cases of extensive CYP2D6 metabolism and concomitant use of CYP2D6 inhibitors, the peak plasma concentration of atomoxetine should be monitored after 1–2 hours. CYP2D6 inhibitors can increase atomoxetine blood levels, which increases both the likelihood of a response and the risk of side effects. When CYP2D6 inhibitors are administered alongside atomoxetine in people with ADHD who have genetically enhanced CYP2D6 metabolism, atomoxetine blood levels should be monitored regularly.92

9.1.3. CYP2D6 inhibitors

CYP2D6 metabolizes, among other things:93

  • Class I antiarrhythmic drugs
  • Beta-blockers
  • HT3 receptor antagonists
  • Amphetamine and its derivatives
  • Opioids

CYP2D6 inhibitors include, among others:

  • Fluoxetine (strong)9293
  • Paroxetine (strong)9293
    • Paroxetine increased the plasma levels of atomoxetine by a factor of 5.8.94
  • Bupropion (moderate)92
  • Duloxetine (moderate)92
  • Sertraline93; questionable95

9.1.4. CYP2D6 gene variants influence the effects of atomoxetine and MPH

Different CP gene variants have a significant impact on the efficacy of ATX and MPH:96

An improvement in symptoms following atomoxetine was observed in patients with CYP2D6 gene variants

  • rs1135840 ‘CC’
  • rs28363170 9R

In contrast, an improvement in ADHD symptoms following MPH administration was observed in the CYP2D6 gene variants

  • rs1065852 ‘GG’
  • rs1135840 ‘CG’
  • rs28363170 10R

10. Long-term effects: No tolerance effects associated with atomoxetine

A meta-analysis of 87 randomized, placebo-controlled, double-blind studies found no evidence of a decline in the efficacy of methylphenidate, amphetamine-based medications, atomoxetine, or α2-antagonists with long-term use.97

11. Discontinuation of Atomoxetine

Studies found no evidence of withdrawal symptoms. Tapering off the medication was not deemed necessary. There was a slight tendency toward more side effects when the medication was tapered off gradually in adults.98
In our experience, tapering off atomoxetine gradually reduces the risk of withdrawal symptoms.

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