Atomoxetine for ADHD

Earlier names of atomoxetine were: Tomoxetine, LY139603

Brand name: Strattera; several generics ¹

• 1. Impact path
  • 1.1. Effect of atomoxetine in the PFC
  • 1.2. No dopaminergic effect of atomoxetine in the striatum/nucleus accumbens
  • 1.3. Other areas of influence of atomoxetine
  • 1.4. Effect of atomoxetine different from MPH
  • 1.5. Specific effect on hyperactivity/impulsivity
  • 1.6. Overview of ATX and neurotransmitters
    • 1.6.1. Binding affinity of ATX, AMP, MPH to DAT / NET / SERT
    • 1.6.2. Effect of ATX, AMP, MPH on dopamine / norepinephrine per brain region
• 2. Impact quality
• 3. Indications for which atomoxetine is suitable / unsuitable
  • 3.1. Nonresponding to stimulants
  • 3.2. Emotional dysregulation
  • 3.3. Comorbid anxiety disorder
  • 3.4. Comorbid social phobia
  • 3.5. SCT (sluggish cognitive tempo)
  • 3.6. Comorbid depression: ATX unsuitable
  • 3.7. Comorbid addiction: Preference of ATX disputed
  • 3.8. ATX in pregnancy
• 4. Dosage
• 5. Responding
• 6. Side effects
  • 6.1. ATX and blood pressure
  • 6.2. ATX increases histamine
  • 6.3. Other side effects of ATX
• 7. Reduction of ATX
• 8. Interactions
  • 8.1. Atomoxetine and CYP2D6
    • 8.1.1. In affected individuals with genetically weak CYP2D6 metabolism
      • 8.1.1.1. Atomoxetine without CYP2D6 inhibitors
      • 8.1.1.2. Atomoxetine with concomitant use of CYP2D6 inhibitors
    • 8.1.2. In sufferers with genetically elevated CYP2D6 metabolism
      • 8.1.2.1. Atomoxetine without CYP2D6 inhibitors
      • 8.1.2.2. Atomoxetine with concomitant use of CYP2D6 inhibitors
    • 8.1.3. CYP2D6 inhibitors
    • 8.1.4. CYP2D6 -gene variants influence effect of ATX and MPH
• 9. Long-term effects: No habituation effects of atomoxetine

1. Impact path¶

Atomoxetine requires a flare-up of several weeks, as is known from common antidepressants. It may take up to 6 months for maximum effect.² According to other sources, the effect of atomoxetine sets in within 4 weeks (possibly within 1 week in later responders). it takes at least 12 weeks to reach full effect.³

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

1.1. Effect of atomoxetine in the PFC¶

In the laboratory, atomoxetine appears to act primarily as a norepinephrine (transporter) reuptake inhibitor. The results in vivo differ from this.⁴

In addition, it should be noted that the noradrenaline transporter can also reuptake dopamine, just as the dopamine transporter can also transport noradrenaline.

Atomoxetine

• Increases extracellular norepinephrine in the PFC 3-fold⁵⁶
• Increases extracellular dopamine in the PFC 3-fold⁵⁶⁷
• May also act as a serotonin reuptake inhibitor
  • A study in live monkeys found that atomoxetine addressed the serotonin transporter at about the same strength as the norepinephrine transporter, so atomoxetine also acted as a serotonin reuptake inhibitor.⁸
• Increases the expression of the neuronal activity marker Fos in the PFC by 3.7-fold⁵⁶

The effect of atomoxetine in the PFC explains the improvement in working memory and executive functions.⁹ A single dose reduces the activity of the vmPFC in relation to reward evaluation.¹⁰
The noradrenaline increase by atomoxetine in PFC is hardly dose-dependent and therefore very difficult to achieve in a graded manner. The noradrenaline increase by D-amphetamine in PFC, on the other hand, is much more dose-dependent and therefore seems to be much more controllable.⁷

1.2. No dopaminergic effect of atomoxetine in the striatum/nucleus accumbens¶

Atomoxetine causes

• No dopamine increase in the striatum⁷⁵⁶
• Therefore no increase in dopamine in the nucleus accumbens⁷⁵⁶
• No increase in the expression of the neuronal activity marker Fos in the striatum or nucleus accumbens
• (as a single dose) did not alter nucleus accumbens activity related to reward expectancy.¹⁰
• Therefore, no improvements on hyperactivity/impulsivity and motivation (drive) are expected via this route of action. Atomoxetine appears to have other pathways with respect to hyperactivity and impulsivity.

1.3. Other areas of influence of atomoxetine¶

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. DAT are mainly responsible in the striatum for the degradation of dopamine.⁷ The smaller the inhibition constant Ki, the higher the affinity.

• Atomoxetine (3 mg/kg i.p.) increased in rats¹¹
  • 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 an attenuating effect of adrenergic autoreceptors on norepinephrine release.
    • Cortex occipital
    • Hypothalamus lateral
    • Hippocampus dorsal
    • Cerebellum
  • extracellular dopamine
    • PFC
    • ATX also did not increase dopamine in the lateral hypothalamus and occipital cortex, where dopamine was detectable. Therefore, a specific mode of action in the PFC can be assumed.

• Acts as NMDA glutamate receptor antagonist¹²
• Does not change the extracellular serotonin level

Consequently, contrary to other assumptions, atomoxetine is not a pure norepinephrine reuptake inhibitor with no effect on dopamine balance.¹³

One study investigated the effect of an ATX-/D-serine combination in relation to goal-directed attention in rats, which is thought to
is supported by glutamatergic and noradrenergic systems. While low-dose ATX as well as low-dose D-serine alone showed 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 can be facilitated by simultaneously affecting glutamatergic and noradrenergic systems.¹⁴
The result is in exciting contrast to the fact that ATX also acts as an NDMA antagonist.

1.4. Effect of atomoxetine different from MPH¶

Methylphenidate

• Increases extracellular norepinephrine in the PFC (like atomoxetine)⁵
• Increases extracellular dopamine in the PFC (like atomoxetine)⁵
• Unclear whether MPH increases extracellular dopamine also in the striatum and there in the nucleus accumbens (different from atomoxetine)
  • Increase of extracellular dopamine also in the striatum and there in the nucleus accumbens⁵¹⁵
    • MPH responders exhibit increased DAT count in the striatum, whereas MPH nonresponders exhibit decreased DAT count in the striatum. ¹⁶
  • No dopamine increase in the striatum by MPH¹⁷

The nucleus accumbens is part of the striatum, the brain’s reward/reinforcement system, which is involved in ADHD. Therefore, in those with acute addiction problems, atomoxetine may have advantages. If the reward system is impaired, methylphenidate and possibly nicotine (patches) are likely to be more effective.

1.5. Specific effect on hyperactivity/impulsivity¶

Hyperactivity and impulsivity can also be caused by overexpression of the ATXN7 gene in the PFC and striatum.¹⁸ Atomoxetine was able to resolve the hyperactivity and impulsivity in this case.

Methylphenidate and amphetamine drugs increase the power of alpha in the EEG (in rats), whereas atomoxetine and guanfacine do not.¹⁹

1.6. Overview of ATX and neurotransmitters¶

1.6.1. Binding affinity of ATX, AMP, MPH to DAT / NET / SERT¶

The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP) and atomoxetine (ATX) bind with different affinities to dopamine transporters (DAT), noradrenaline transporters (NET) and serotonin transporters (SERT). The binding causes inhibition of the activity of the respective transporters.²⁰

Binding affinity: stronger with smaller number (KD = Ki)	DAT	NET	SERT
MPH	34 - 200	339	> 10,000
d-AMP (Elvanse, 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

1.6.2. Effect of ATX, AMP, MPH on dopamine / norepinephrine per brain region¶

The drugs methylphenidate (MPH), amphetamine (AMP), and atomoxetine (ATX) alter extracellular dopamine (DA) and norepinephrine (NE) differently in different brain regions. Table based on Madras,²⁰ modified.

	PFC	striatum	nucleus accumbens	cortex occipital	hypothalamus lateral	hippocampus dorsal	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, the DAT binds dopamine much better than norepinephrine.
Nevertheless, atomoxetine increases dopamine only in the PFC and not everywhere it binds to the NET, so there appears to be a specific mechanism of action here.

2. Impact quality¶

In MPH nonresponders, lisdexamfetamine and atomoxetine were compared in a randomized double-blind trial with n = 200 subjects. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.²¹

Atomoxetine produces a 3.8-point reduction in ADHD RS-IV total score, compared with 8.9 by guanfacine.²²

In affected person forums, quite a few (but not all) atomoxetine users report that atomoxetine only had excellent effects in the first few days, up to a maximum of about 14 days, which then had clearly diminished or disappeared completely. This could repeat itself after dosage increases, even several times.²³ We believe that this is a pattern that occurs more often in ADHD with primarily tonic noradrenergic medications and suspect that this indicates that in ADHD in general, and in the respective sufferers in particular, the phasic noradrenaline level is impaired rather than the tonic one.
Phasic is the short-term (stress or exertion occasion-related) altered level of a neurotransmitter or hormone.
Tonic is the permanent level and its typical circadian level changes throughout the day.
Phasic behaves to tonic like waves to swell.

For the efficacy of individual medications and forms of treatment, see ⇒ Effect size of different forms of treatment for ADHD.

3. Indications for which atomoxetine is suitable / unsuitable¶

3.1. Nonresponding to stimulants¶

Atomoxetine is widely believed to be recommended when neither methylphenidate nor amphetamines work, which is reported to be the case in 17%²⁴ to 33%²⁵ of ADHD sufferers. We suggest testing guanfacine beforehand, especially in younger children and in sufferers with hypertension, as guanfacine has a better mean effect size with lower side effects than atomoxetine.
About 50% of sufferers who do not respond to MPH should respond to atomoxetine, and about 75% of sufferers who respond to MPH should also respond to atomoxetine.²⁶

3.2. Emotional dysregulation¶

Only the ADHD symptom of lack of inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen), whereas lack of inhibition of emotion regulation is caused noradrenergically by the hippocampus.²⁷ Therefore, the former is likely to be more amenable to dopaminergic treatment, whereas emotion regulation and affect control are likely to be better treated noradrenergically.
This is consistent with empirical experience that atomoxetine treats emotional dysregulation much better (and especially all day) than stimulants. On the other hand, because of the lack of dopaminergic effect in the striatum, atomoxetine has a lower drive enhancement than stimulants, which is why a combination medication is often the key to success of a complete ADHD treatment.

3.3. Comorbid anxiety disorder¶

Positive effects of atomoxetine on comorbid anxiety disorders have been reported,²⁸ with one study finding slightly greater improvement in anxiety symptomatology with atomoxetine than with MPH.²⁹

3.4. Comorbid social phobia¶

Positive effects of atomoxetine on comorbid social anxiety have been reported.²⁸

3.5. SCT (sluggish cognitive tempo)¶

In one study, atomoxetine significantly improved 7 of 9 Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) symptoms in SCT. Symptom improvement in SCT was completely independent of ADHD symptoms.³⁰

SCT sufferers are also particularly frequent MPH nonresponders. In contrast, the ADHD-HI and ADHD-I subtypes do not differ in MPH response rates.³¹

3.6. Comorbid depression: ATX unsuitable¶

Atomoxetine does not appear to be suitable for the treatment of comorbid depression.³²

When taking SSRIs concomitantly, the possible interaction via CYP2D6 should be noted (see below).

3.7. Comorbid addiction: Preference of ATX disputed¶

While one opinion favors atomoxetine in comorbid addiction due to the lower risk of abuse, another view sees advantages with stimulants due to the faster effect and greater effect size. That stimulants in ADHD do not increase the risk of addiction but significantly reduce it during use is now well established, according to the updated 2018 European consensus on the diagnosis and treatment of ADHD in adults.³²

3.8. ATX in pregnancy¶

One study found no increase in major congenital malformations, cardiac malformations, or limb malformations after atomoxetine exposure in the first trimester of pregnancy.³³

4. Dosage¶

Dosing is as individual as with MPH or AMP. Reports of individual dosing based on a blood level have not been confirmed to a precise degree required for therapeutic use.³⁴

Factors affecting the pharmacokinetics of atomoxetine are discussed as:³⁴

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

5. Responding¶

Atomoxetine produced significant improvements in approximately 45% of sufferers in a placebo study, compared with 58% responders to Concerta (MPH) and 28% to placebo.³⁵

One study examined the EEG structure of atomoxetine responders and nonresponders. According to this study, atomoxetine works better in those who have increased alpha and delta power in the frontal and temporal areas and who, at the same time, have no deviations in the beta and theta bands. In contrast, atomoxetine nonresponders showed decreased absolute power in all EEG frequencies or increased alpha and simultaneously increased beta power. Atomoxetine caused long-term normalization of the elevated alpha and delta values, whereas these remained unchanged in nonresponders. In the case of simultaneously elevated alpha, beta, and theta values, atomoxetine appeared unsuitable.³⁶

About 50% of sufferers who do not respond to MPH should respond to atomoxetine, and about 75% of sufferers who respond to MPH should also respond to atomoxetine.²⁶

6. Side effects¶

6.1. ATX and blood pressure¶

Atomoxetine caused an average increase in pulse of 6.4 beats, Concerta (MPH) 3 beats, placebo 0.3 beats.³⁵

Systolic blood pressure increases by an average of 3.7 with atomoxetine, 2.4 with Concerta (MPH), and 1.3 with placebo.³⁵

Diastolic blood pressure increases by an average of 3.8 with atomoxetine, 3.1 with Concerta (MPH), and 0.4 with placebo.³⁵

One large study found no increased risks of serious cardiovascular events such as stroke, heart attack, or arrhythmia for atomoxetine among 2,566,995 children.³⁷

6.2. ATX increases histamine¶

ATX increases histamine,³⁸³⁹ as do all other known ADHD medications:

• Amphetamine drugs
• Methylphenidate
• Modafinil
• Nicotine
• Caffeine

Therefore, people with histamine intolerance often have problems by taking ADHD medications.
One ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but could tolerate sustained-release MPH in small doses.

6.3. Other side effects of ATX¶

Atomoxetine produced a weight loss of 0.6, Concerta (MPH) of 0.9, placebo of 1.1 (i.e., a greater loss than ATX and MPH).³⁵
Atomoxetine has been associated with a low rate of serum aminotransferase elevations and with rare cases of acute, clinically apparent liver injury.⁴⁰

7. Reduction of ATX¶

Atomoxetine is degraded in the liver by the enzyme CYP2D6 (cytochrome P450 2D6). During degradation, a potent intermediate is formed which, like atomoxetine itself, is excreted in the urine.⁴¹

In vitro, the 4-hydroxy-atomoxetine signaling pathway accounted for 98.4% and the N-desmethyl-atomoxetine signaling pathway accounted for 1.5% of atomoxetine metabolism in cryopreserved plated human hepatocytes.⁴²

8. Interactions¶

8.1. Atomoxetine and CYP2D6¶

Metabolism of atomoxetine by CYP2D6 depends on basic genetic parameters and complicates dosing. A study describes the prediction of atomoxetine plasma levels using simple physiologically based pharmacokinetic models.⁴³⁴⁴

8.1.1. In affected individuals with genetically weak CYP2D6 metabolism¶

8.1.1.1. Atomoxetine without CYP2D6 inhibitors¶

Weak CYP2D6 metabolization was found to result in an average of 10-fold atomoxetine blood levels compared with strong CYP2D6 metabolization.
High response to atomoxetine (of 80% according to the manufacturer) with concomitant increased side effects, which, however, usually do not lead to discontinuation of use. Dosing with weak doses (40 mg/day) recommended.⁴⁵ We recommend even much slower dosing (increments of 8 mg / day, increasing every 4 days).

8.1.1.2. Atomoxetine with concomitant use of CYP2D6 inhibitors¶

In the case of weak CYP2D6 metabolism, additional intake of CYP2D6 inhibitors did not further increase the already 10-fold increased atomoxetine blood level, since those affected by genetically weak CYP2D6 metabolism do not have CYP2D6 metabolism.⁴⁵

8.1.2. In sufferers with genetically elevated CYP2D6 metabolism¶

8.1.2.1. Atomoxetine without CYP2D6 inhibitors¶

Strong CYP2D6 metabolization without concomitant use of CYP2D6 inhibitors was found to result in reduced atomoxetine blood levels on average compared to weak CYP2D6 metabolization (plasma concentration peak below 200 ng/ml 1-2 hours after ingestion). Low response to atomoxetine (of 60% according to manufacturer). Dose increase may be required, possibly up to over 100 mg/day in adults.⁴⁵

8.1.2.2. Atomoxetine with concomitant use of CYP2D6 inhibitors¶

If CYP2D6 metabolism is high and CYP2D6 inhibitors are taken concomitantly, the plasma peak atomoxetine concentration should be monitored after 1-2 hours. CYP2D6 inhibitors may increase aomoxetine blood levels, which increases the likelihood of response as well as the risks of side effects. When CYP2D6 inhibitors are administered alongside atomoxetine in sufferers with genetically elevated CYP2D6 metabolism, atomoxetine blood levels should be monitored regularly.⁴⁵

8.1.3. CYP2D6 inhibitors¶

CYP2D6 metabolizes, among others:⁴⁶

• Class I antiarrhythmics
• Beta blocker
• HT3 receptor antagonists
• Amphetamine and derivatives
• Opioids

CYP2D6 inhibitors include:

• Fluoxetine (strong)⁴⁵⁴⁶
• Paroxetine (strong)⁴⁵⁴⁶
  • Paroxetine increased plasma levels of atomoxetine 5.8-fold.⁴⁷
• Bupropion (moderate)⁴⁵
• Duloxetine (moderate)⁴⁵
• Sertraline⁴⁶; dubious⁴⁸

8.1.4. CYP2D6 -gene variants influence effect of ATX and MPH¶

Different CP gene variants show significant influence on the efficacy of ATX and MPH:⁴⁹

Improvement in symptoms after atomoxetine was found in CYP2D6 gene variants

• rs1135840 ’CC
• rs28363170 9R

In contrast, an improvement of ADHD symptoms on MPH administration was found for the CYP2D6 gene variants

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

9. Long-term effects: No habituation effects of atomoxetine¶

A meta-analysis of 87 randomized placebo-controlled double-blind trials found no evidence of diminishing effects of methylphenidate, amphetamine medications, atomoxetine, or α2-antagonists with prolonged use.⁵⁰