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Atomoxetine for ADHD

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Atomoxetine for ADHD

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Former names of atomoxetine were: Tomoxetine, LY139603

Brand name: Strattera; several generics 1

1. Route of action

Atomoxetine requires an onset of several weeks, as is the case with conventional antidepressants. It can take up to 6 months for the maximum effect.2 According to other sources, the effect of atomoxetine sets in within 4 weeks (possibly within 1 week for responders). It takes at least 12 weeks for the effect to be complete.3

It is sometimes reported that depression can occur during the familiarization phase of several weeks with atomoxetine. This probability is higher than with methylphenidate, imipramine, nortriptyline (Nortrilen) or bupropion (Elontril).

1.1. Noradrenaline and dopamine levels increased in the PFC

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

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

Atomoxetine

  • Increases the extracellular noradrenaline in the PFC by a factor of 356
  • Increases extracellular dopamine in the PFC by a factor of 3567

Atomoxetine

  • Has an extremely high affinity for noradrenaline 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 responsible for the reuptake of dopamine in the PFC, whereas DATs are primarily responsible for the reuptake of dopamine in the striatum.7 The smaller the inhibition constant Ki, the higher the affinity.
  • Atomoxetine (3 mg/kg i.p.) increased in rats8
    • extracellular norepinephrine significantly in
      • PFC
        • Administration of the alpha(2)-adrenergic antagonist idazoxan one hour after atomoxetine further increased the release of noradrenaline in the PFC. This suggests an attenuating effect of the adrenergic autoreceptors on noradrenaline release.
        • chronic administration attenuated the increase in extracellular noradrenaline in the PFC9
      • Occipital cortex
      • Lateral hypothalamus
      • Dorsal hippocampus10
      • Cerebellum
    • extracellular dopamine
      • PFC
      • not in the lateral hypothalamus
      • not in the occipital cortex
      • not in the hippocampus10

In SHR and Wistar-Kyoto rats, atomoxetine increased extracellular dopamine and noradrenaline in the PFC.11

Atomoxetine increases the expression of the neuronal activity marker Fos in the PFC by 3.7-fold.56

Contrary to other assumptions, atomoxetine is therefore not a pure noradrenaline reuptake inhibitor with no effect on the dopamine balance.12

The effect of atomoxetine in the PFC explains the improvement in working memory and executive functions.13 A single dose reduces the activity of the vmPFC in relation to reward evaluation.14
The noradrenaline increase by atomoxetine in PFC is less dose-dependent than with other drugs and therefore more difficult to achieve in a graded manner.7 A measurement of noradrenaline reuptake inhibition based on the attenuation of systolic blood pressure by i.v. injections of tyramine showed a significant noradrenaline reuptake inhibition with ATX, which was even more pronounced than that of venlaflaxine and which was more pronounced even at low doses (25 mg/day).15 In contrast, the noradrenaline increase caused by D-amphetamine in the PFC is much more dose-dependent and therefore appears to be much more controllable7

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

Atomoxetine causes

  • No dopamine increase in the striatum756
  • Therefore no dopamine increase in the nucleus accumbens756
  • 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 expectation (as a single dose)14

Therefore, no improvements in hyperactivity/impulsivity and motivation (drive) are to be expected via this route of action. Atomoxetine apparently has other pathways of action in relation to hyperactivity and impulsivity.

1.3. Serotonin at Atomoxetine

Atomoxetine apparently also acts as a serotonin reuptake inhibitor

  • A study in living monkeys found that atomoxetine addressed the serotonin transporter at about the same strength as the noradrenaline transporter, so that atomoxetine also acted as a serotonin reuptake inhibitor.16
  • Another study also reported binding to the SERT by atomoxetine.15 However, the reduction in serotonin levels in whole blood was significantly lower (-40%) than with paroxetine or venlaflaxine (-95%). The improvement in depression symptoms corresponded to that of paroxetine and venlaflaxine. The reduction did not depend on the SERT genotype.

However, atomoxetine does not alter the level of extracellular serotonin

  • in the PFC5119
  • in the striatum9
  • in the hippocampus10

The rare cases of increased suicidality when taking atomoxetine are consistent with those of SSRIs, which indicates a serotonergic effect.17

1.4. NMDA glutamate receptor antagonist

Atomoxetine acts as an NMDA glutamate receptor antagonist.18

One study investigated the effect of an ATX/D-serine combination on goal-directed attention in rats, which is thought to
is supported by glutamatergic and noradrenergic systems. While low-dose ATX and 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 influencing glutamatergic and noradrenergic systems.19
The result is in exciting contrast to the fact that ATX also acts as an NDMA antagonist.

1.5. Effect of atomoxetine different from MPH

Methylphenidate

  • Increases extracellular noradrenaline in the PFC (like atomoxetine)5
  • Increases extracellular dopamine in the PFC (like atomoxetine)5
  • Unclear whether MPH also increases extracellular dopamine in the striatum and there in the nucleus accumbens (unlike atomoxetine)
    • Increase in extracellular dopamine also in the striatum and there in the nucleus accumbens520
      • MPH responders show an increased DAT count in the striatum, while MPH non-responders show a reduced DAT count in the striatum. 21
    • No dopamine increase in the striatum due to MPH22
  • Methylphenidate and atomoxetine increase the efficiency of the prefrontal pyramidal neurons, albeit via different mechanisms:23
    • Methylphenidate reduced non-specific signals, i.e. neuronal noise, via D1 receptors
    • Atomoxetine increased the strength of specific signals via 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 have advantages for patients with acute addiction problems. If the reward system is impaired, methylphenidate and possibly nicotine (patches) may be more effective.

1.6. Specific mode of action on hyperactivity/impulsivity

Hyperactivity and impulsivity can also be caused by overexpression of the ATXN7 gene in the PFC and striatum.24 In this case, atomoxetine was able to eliminate the hyperactivity and impulsivity.

Methylphenidate and amphetamine drugs increase the power of alpha in the EEG (in rats), while atomoxetine and guanfacine do not.25

Atomoxetine, like citalopram, is not expected to improve reaction time variability and response inhibition, unlike MPH.26

1.7. Overview of ATX and neurotransmitters

1.7.1. 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 an inhibition of the activity of the respective transporters.27

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

1.7.2. Effect of ATX, AMP, MPH on dopamine / noradrenaline per brain region

The active substances methylphenidate (MPH), amphetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different regions of the brain. Table based on Madras,27 modified.

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 noradrenaline, the DAT binds dopamine much better than noradrenaline.
However, atomoxetine only increases dopamine in the PFC and not everywhere where it binds to the NET, so that there appears to be a special mechanism of action here.

2. Impact quality

In MPH non-responders, lisdexamfetamine and atomoxetine were compared in a randomized double-blind study with n = 200 subjects. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.28

Atomoxetine reduces the ADHD-RS-IV total score by 3.8 points, compared to 8.9 with guanfacine.29

Many (but not all) Atomoxetine users report in patient forums that Atomoxetine only had excellent effects for the first few days, up to a maximum of around 14 days, which then diminished significantly or disappeared completely. This could be repeated after increasing the dosage, even several times.30 We believe that we can recognize a pattern here that occurs more frequently with drugs with a primarily tonic noradrenergic effect in ADHD and suspect that this indicates that the phasic noradrenaline level is impaired in ADHD in general and in the respective patients in particular rather than the tonic level.
Phasic is the short-term change in the level of a neurotransmitter or hormone (during stress or exertion).
Tonic is the permanent level and its typical circadian level changes throughout the day.
Phasic relates to tonic like waves to swell.

If the long-lasting noradrenaline level is in order, an increase regularly causes receptor downregulation, i.e. a compensatory adjustment of the receptors in the direction of reduced sensitivity.
As an unverified hypothesis, we are considering whether intermittent administration (every 2 to 4 days or interruption of administration every 3 days) could prevent such receptor adaptations. Patients in whom atomoxetine has led to such adaptation reactions could discuss this with their doctor. Experiments not agreed with the doctor are strongly discouraged!

For the effectiveness of individual medications and forms of treatment, see ⇒ Effect strength of different forms of ADHD treatment.

3. Indications for which atomoxetine is suitable / unsuitable

3.1. Nonresponding to stimulants

Atomoxetine is widely recommended if neither methylphenidate nor amphetamines are effective, which is said to be the case for 17%31 to 33%32 of ADHD sufferers. We suggest testing guanfacine first, especially in younger children and those with high blood pressure, as guanfacine has a better mean effect size with fewer side effects than atomoxetine.
About 40%33 to 50%34 of those who do not respond to MPH should respond to atomoxetine, and about 75% of those who respond to MPH should also respond to atomoxetine.34

3.2. Emotional dysregulation

Only the ADHD symptom of lack of inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen), while the lack of inhibition of emotion regulation is caused noradrenergically by the hippocampus.35 Therefore, the former may be more amenable to dopaminergic treatment, while emotion regulation and affect control may be more amenable to noradrenergic treatment.
This is consistent with the empirical experience that atomoxetine treats emotional dysregulation much better (and above all for the whole day) than stimulants. However, due to the lack of dopaminergic effects in the striatum, atomoxetine has a lower drive increase than stimulants, which is why combination medication is often the key to the success of complete ADHD treatment.

3.3. Comorbid anxiety disorder

Positive effects of atomoxetine on comorbid anxiety disorders have been reported,36 although one study found a slightly greater improvement in anxiety symptoms with atomoxetine than with MPH.37

3.4. Comorbid social phobia

Positive effects of atomoxetine on comorbid social anxiety have been reported.36

3.5. SCT (sluggish cognitive tempo)

In one study, atomoxetine significantly improved 7 out of 9 symptoms of the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) in SCT. The symptom improvement in SCT was completely independent of the ADHD symptoms.38

SCT sufferers are also particularly frequent MPH non-responders. In contrast, the ADHD-HI and ADHD-I subtypes do not differ in the MPH response rate.39

3.6. Comorbid depression

Whether atomoxetine has an effect on depression is controversial. There are voices against it4041 42 as well as for it. In one study, the improvement in depression symptoms corresponded to that of paroxetine and venlaflaxine.4344
One study found evidence of an effect of atomoxetine together with sertraline in HTTLPR (SERT) genotype s/s compared to sertraline monotherapy 45

When taking SSRIs at the same time, the possible interaction via CYP2D6 should be taken into account (see below).

3.7. Comorbid addiction: Preference for ATX disputed

While one opinion favors atomoxetine for comorbid addiction due to the lower risk of abuse, another opinion sees advantages in stimulants due to the faster effect and greater effect strength. According to the updated European consensus on the diagnosis and treatment of ADHD in adults from 2018, it is now well established that stimulants do not increase the risk of addiction in ADHD, but instead significantly reduce it during use.41

3.8. ATX during pregnancy

One study found no increase in major congenital malformations, cardiac malformations or limb malformations after exposure to atomoxetine in the first trimester of pregnancy.46

4. Dosage

Dosing is as individualized as with MPH or AMP. Reports of individual dosing based on blood levels have not been confirmed to the degree of accuracy required for therapeutic use.47
It can be taken as a single daily dose in the morning or in two equal doses in the morning and late afternoon/early evening. A single evening dose resulted in reduced side effects with reduced efficacy40
The total daily dose for children and adolescents should not exceed 1.8 mg/kg, but not more than 100 mg per day.40 A meta-study reports an increase in the effect of ATX up to a dose of 1.4 mg/kg, after which a plateau occurs48

Factors influencing the pharmacokinetics of atomoxetine are discussed:47

  • Foodstuffs
  • Interactions between medications
  • CYP2D6 gene variants
  • CYP2C19 gene variants
  • NET gene variants
  • Dopamine β-hydroxylase gene variants

ATX is also safe and effective in combination with stimulants.49

5. Duration until onset of action

The full effect of ATX only becomes apparent after 6 to 8 weeks of treatment or later. Responders usually show some change after 4 weeks. Once full clinical efficacy is achieved, it appears to persist at a relatively constant level throughout the day.40

In our experience, many patients experience an initial effect within the first week.
One affected person even took ATX only on individual days and reported a day-related effect. However, we expressly do not recommend this, as we have evidence of a risk of depression here.

6. Addressing / Responding

Response means whether there is an effect on the ADHD symptoms. Patients who do not respond sufficiently to a medication are called non-responders. Nonresponding does not mean having no effect, but merely that the effect remains below the level of symptom improvement specified in the respective study.

In a placebo study, atomoxetine brought about significant improvements in around 45% of those affected, compared with 58% responders to Concerta (MPH) and 28% to placebo.50

The median time to response with a 25% improvement in ADHD symptoms was 3.7 weeks in pooled studies. The likelihood of symptom improvement may continue to increase up to 52 weeks after the start of treatment.49

One study examined the EEG structure of atomoxetine responders and non-responders. According to the study, atomoxetine works better in those who have increased alpha and delta power in the frontal and temporal areas and in whom there are no deviations in the beta and theta bands. Atomoxetine non-responders, on the other hand, showed reduced absolute power in all EEG frequencies or increased alpha and simultaneously increased beta power. In the long term, atomoxetine caused a normalization of the excessive alpha and delta values, while these remained unchanged in non-responders. Atomoxetine appeared unsuitable in the case of simultaneously elevated alpha, beta and theta values.51

About 40% to 50% of patients who do not respond to MPH are expected to respond to atomoxetine, and about 75% of patients who respond to MPH are expected to respond to atomoxetine.34

7. Side effects

7.1. ATX and cardiovascular problems

Atomoxetine caused an average increase in heart rate of 6.4 beats, Concerta (MPH) of 3 beats and placebo of 0.3 beats.50

Systolic blood pressure increased on average by 3.7 with atomoxetine, by 2.4 with Concerta (MPH) and by 1.3 with placebo.50

Diastolic blood pressure increased on average by 3.8 with atomoxetine, by 3.1 with Concerta (MPH) and by 0.4 with placebo.50

A large study found no increased risk of serious cardiovascular events such as stroke, heart attack or cardiac arrhythmia for atomoxetine among 2,566,995 children.52
One study found an increased risk of cardiac arrhythmias during the first 7 days after 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.53

A study over 14 years found a 4% increase in the risk of cardiovascular problems per year of taking stimulants (methylphenidate, amphetamines) and, to a lesser extent, non-stimulant atomoxetine.54

One study found no prolongation of QTcF or QTcB to more than 500 ms or an increase of more than 60 ms.55

7.2. ATX increases histamine

ATX increases histamine,5657 like all other known ADHD medications:

  • Amphetamine drugs
  • Methylphenidate
  • Modafinil
  • Nicotine
  • Caffeine

This is why people with histamine intolerance often have problems when taking ADHD medication.
An ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but was able to tolerate low doses of sustained-release MPH.

7.3. Other side effects of ATX

Atomoxetine caused a weight loss of 0.6, Concerta (MPH) of 0.9, placebo of 1.1 (i.e. a greater weight loss than ATX and MPH).50
Atomoxetine has been associated with a low rate of serum aminotransferase elevations and with rare cases of acute, clinically apparent liver injury.58

Studies found side effects of atomoxetine (in % of patients affected):

  • Loss of appetite 14.9 %59
  • Insomnia: 11.3 %59
  • erectile dysfunction: 8.0 vs. 1.9 % with placebo60
  • Urinary retention: 6.9 % vs. 2.4 % with placebo60
  • Drowsiness: 6.0 %59
  • decreased libido: 4.6 % compared to 3.0 % with placebo60
  • Dysuria: 3.7 % vs. 1.5 % with placebo60
  • Ejaculation disorders: 2.8 vs. 1.1 % with placebo60
  • reduced urine flow: 2.5 % vs. 0.6 % with placebo60

The sexual and urological disorders are related to the possible non-selective peripheral effect on the adrenergic nerve endings in the smooth muscle cells of the sphincter and urethral arteries.61 Atomoxetine improved nocturnal enuresis in children.62

8. Reduction of ATX

8.1. Degradation with normal CYP2D6 levels

The main degradation pathway of atomoxetine (98.4 %)63 takes place in the liver by the enzyme CYP2D6 (cytochrome P450 2D6) to 4’-hydroxyatomoxetine, which is just as effective as atomoxetine itself. In addition to CYP2D6 (which converts ATX 475 times faster than the other enzymes)64, CYP2C19, CYP3A, CYP1A2, CYP2A6 and CYP2E1 are involved in the metabolization to 4’-hydroxyatomoxetine65

4’-Hydroxyatomoxetine is glucuronidated to the inactive 4’-hydroxyatomoxetine-O-glucuronide.66

A secondary degradation pathway with 1.5 %63 is N-desmethylation. This occurs mainly through CYP2C1964

Another degradation pathway is benzyl oxidation.65

8.2. Degradation with reduced CYP2D6 levels

In individuals with moderate or poor CYP2D6 metabolism, ATX can also be converted (in vitro) to 4’-hydroxyatomoxetine by CYP2E1 and CYP2E1 and CYP3A. In the poorest metabolizers, biotransformation by CYP2B6 to 2-hydroxymethylatomoxetine (2-CH2OH-ATX) predominates.67 However, the overall clearance of ATX remained impaired in poor CYP2D6 metabolizers.
With extensive CYP2D6 metabolism, the majority of ATX was excreted within 24 hours, with poor CYP2D6 metabolism within 72 hours.68

In children, the metabolism of ATX is impaired by CYP2D6. In vitro production of alternative metabolites (N-desmethylatomoxetine and 2-hydroxymethylatomoxetine) was observed.68 This is in contrast to studies that observed an age-dependent impairment of CYP2D6 metabolization only in the first one or two weeks of life.67

The effectiveness of CYP2D6 degradation is influenced by gene variants of the POR gene (cytochrome P450 oxidoreductase)69

More on this under CYP2D6 metabolizing enzyme And Effect and duration of action of ADHD medications.

9. Interactions

9.1. Atomoxetine and CYP2D6

The 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.7071

9.1.1. In patients with genetically weak CYP2D6 metabolization

9.1.1.1. Atomoxetine without CYP2D6 inhibitors

With weak CYP2D6 metabolization, the average blood level of atomoxetine was 10 times higher than with strong CYP2D6 metabolization.
High response to atomoxetine (of 80 % according to the manufacturer) with increased side effects, which, however, usually do not lead to discontinuation of use. Dosing with low doses (40 mg/day) recommended72
We know of cases of side effects that could be significantly reduced by slow dosing (steps of 8 mg / day, increasing every 4 days).

9.1.1.2. Atomoxetine with concomitant use of CYP2D6 inhibitors

In the case of weak CYP2D6 metabolization, an additional intake of CYP2D6 inhibitors did not further increase the already 10-fold increased atomoxetine blood level, since those affected by genetically weak CYP2D6 metabolization have no CYP2D6 metabolization.72

9.1.2. In patients with genetically increased CYP2D6 metabolization

9.1.2.1. Atomoxetine without CYP2D6 inhibitors

With strong CYP2D6 metabolization without simultaneous intake of CYP2D6 inhibitors, atomoxetine blood levels were found to be reduced on average compared to weak CYP2D6 metabolization (plasma concentration peak below 200 ng/ml 1-2 hours after intake). Low response to atomoxetine (of 60 % according to the manufacturer). Dose increase may be necessary, possibly to over 100 mg/day in adults.72

9.1.2.2. Atomoxetine with concomitant use of CYP2D6 inhibitors

In the case of strong CYP2D6 metabolization and concomitant intake of CYP2D6 inhibitors, the aomoxetine plasma peak concentration should be checked after 1-2 hours. CYP2D6 inhibitors can increase aomoxetine blood levels, which increases the probability of response as well as the risk of side effects. When administering CYP2D6 inhibitors in addition to atomoxetine in patients with genetically increased CYP2D6 metabolization, atomoxetine blood levels should be monitored regularly.72

9.1.3. CYP2D6 inhibitors

CYP2D6 metabolizes among others:73

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

CYP2D6 inhibitors are among others:

  • Fluoxetine (strong)7273
  • Paroxetine (strong)7273
    • Paroxetine increased the plasma level of atomoxetine by 5.8 times.74
  • Bupropion (moderate)72
  • Duloxetine (moderate)72
  • Sertraline73; doubtful75

9.1.4. CYP2D6 gene variants influence the effect of ATX and MPH

Different CP gene variants show significant influence on the efficacy of ATX and MPH:76

An improvement in symptoms after atomoxetine was found in the CYP2D6 gene variants

  • rs1135840 ‘CC’
  • rs28363170 9R

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

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

10. Long-term effect: No habituation effects of atomoxetine

A meta-analysis of 87 randomized placebo-controlled double-blind studies found no evidence of a decrease in the effect of methylphenidate, amphetamine drugs, atomoxetine or α2 antagonists with prolonged use.77

11. Discontinuation of atomoxetine

Studies found no evidence of discontinuation symptoms. Tapering was not found to be necessary. There was a slight tendency towards higher side effects with graduated dosing in adults.78

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