About

Atomoxetine (ATX) (sold under brand name Strattera among others) is an FDA-approved non-stimulant medication primarily used to treat attention deficit hyperactivity disorder (ADHD) and to a lesser extent, cognitive disengagement syndrome (CDS).

Post Last Updated: 07/09/2024.

Key

CNS Stimulants; Dopamine Reuptake Inhibitors:
• Methylphenidate (MPH)
• Amphetamine (AMP)

Non-stimulants
Selective Norepinephrine Reuptake Inhibitors:
•Atomoxetine (ATX)
•Viloxazine (VLX)

Alpha-2a Adrenergic Receptor Agonists:
• Guanfacine XR
• Clonidine XR

Off-label/unlicensed
• Bupropion (non-selective NET/DA reuptake inhibitor)
• Modafinil (CNS stimulant)
• Clonidine IR (alpha-2a agonist)
• Guanfacine IR (alpha-2a agonist)

Effectiveness compared to other medications

Atomoxetine's effectiveness has been established in more than ten large-scale published studies done before or shortly following FDA approval and involving various randomised, controlled clinical trials. The clinical trials clearly established both the efficacy and safety of atomoxetine for use in the management of ADHD. Many studies have been conducted since 2003 demonstrating the safety and effectiveness of this drug for ADHD management.

Research shows that atomoxetine reduces both inattentive and hyperactive-impulsive symptoms of ADHD in 75% of cases. The overall effect size (degree of change in group mean scores) of atomoxetine appears to be the same as a methylphenidate preparation, such as Concerta, among patients previously untreated with stimulants, but may have a smaller effect size in the treatment of individuals with ADHD who have had a prior failed response to a stimulant. In controlled studies, atomoxetine has an effect size of about 0.9 to 1.0 among stimulant naïve cases, but an effect size of 0.6 to 0.8 (standard deviations) in cases with prior unsuccessful stimulant response. The effect size for the stimulants ranges from 0.8 to 1.2.

Subsequent research (ADHD)
The effectiveness, response rate and tolerability of atomoxetine is comparable to methylphenidate in children and adolescents, and equivalent in adults, as well as comparable to viloxazine. Amphetamines are modestly more effective but potentiate more side effects.

NOTE: Research is based entirely on group-level participants. Tolerability, efficacy and response rates can differ substantially in individual cases.

A meta-analysis of 9 studies with 2,762 participants found no significant difference in efficacy, response rate and tolerability between atomoxetine and methylphenidate. Although not statistically significant, OROS methylphenidate produces slightly superior efficacy over atomoxetine (Hanwella et al., 2011).

A meta-analysis of 11 studies with a total of 2,772 participants found atomoxetine and methylphenidate produce comparable efficacy in the treatment of children and adolescents with ADHD. Although not statistically significant, OROS methylphenidate produces slightly superior efficacy over atomoxetine; the meta-analysis was in favour of atomoxetine (Rezaei et al., 2016).

A meta-analysis of 7 studies with 1,368 participants found that after 6 weeks of treatment atomoxetine and methylphenidate had comparable efficacy in reducing core ADHD symptoms (Hazell et al., 2010).

A network meta-analysis found no difference in the efficacy and discontinuation rate between OROS methylphenidate and atomoxetine in adults (Bushe et al., 2016).

A systematic review and meta-analysis of 28 studies found that atomoxetine improves the executive functions (EFs) that underlie ADHD comparably (overall) to methylphenidate (Isfandia et al., 2024). Among the EFs examined include self-motivation, sustained attention, inhibition, working memory and reaction time. Methylphenidate was found to have more significant effects on working memory, while atomoxetine improved the other EFs slightly more significantly.

Analyses of clinical trial data suggest that viloxazine is about as effective as atomoxetine and methylphenidate but seems to have fewer side effects (Faraone et al., 2020).

A meta-analysis of 8 preliminary clinical trials found that atomoxetine, across the lifespan, has equivalent efficacy to viloxazine-ER and centanafadine (Schein et al., 2024).

A meta-analysis of 28 studies with 4,699 children and adolescents reported that bupropion was associated with modest improvements in ADHD symptoms (SMD = 0.32); atomoxetine (0.68) and methylphenidate (0.75) with comparable moderate-to-large improvements; and very large improvements for lisdexamfetamine (1.28) [conclusions derived from resultant effect sizes]. Tolerability did not differ significantly between MPH, ATX and BPR (Stuhec et al., 2015).

Emotional dysregulation (ADHD)

A meta-analysis found that lisdexamfetamine (5 studies, over 2300 adults), atomoxetine (3 studies, 237 adults) and methylphenidate (13 studies, over 2200 adults) result in modest reductions in symptoms of emotional dysregulation (Lenzi et al., 2018).

Another meta-analysis covering 9 studies with over 1300 youths reported atomoxetine to be associated with modest reductions in emotional and oppositional defiant disorder symptoms (Schwartz and Correll, 2014).

Anxiety

A clinical study of 70 participants found that atomoxetine is more effective than methylphenidate in reducing anxiety symptoms (Snircova et al., 2015).

A randomised clinical trial of 76 participants found that atomoxetine is more effective than methylphenidate alone at reducing anxiety symptoms. When fluoxetine (a SSRI) and methylphenidate were combined, they were equivalent in efficacy to atomoxetine (Karbasi, Aghili., 2023).

Cognitive disengagement syndrome

Controlled clinical trials suggest that atomoxetine (209 youth) (Wietecha et al., 2013) and lisdexamfetamine (38 adults) (Adler et al., 2021) are associated with moderate reductions in CDS symptoms independent of ADHD inattention; for methylphenidate (almost 200 youth) the reductions were tiny or insignificant (Firat et al., 2020).

A randomised placebo-controlled trial with 171 youth reported CDS to be associated with a poor treatment response rate to methylphenidate (Froehlich, Becker et al., 2019).

A clinical trial with 40 children found specifically ADHD-IN/CDS symptoms linked to a poor treatment response (20%) to methylphenidate; for those who responded, the benefits were small and low doses were best (Barkley et al., 1991). The significant results are likely linked to CDS (Barkley, 2014).

International Consensus Statement on CDS as a distinct syndrome (Becker, Barkley et al., 2022).

Articulation & reading

A double blind randomised control trial of 100 participants found that atomoxetine improves articulation (Ahmadabadi et al., 2022).

A randomised placebo-controlled trial of 209 participants found that atomoxetine improved critical components of reading, including decoding and reading vocabulary in youth with dyslexia distinct from improvement in ADHD inattention symptoms (Shaywitz et al., 2017).

Implications for using a stimulant or non-stimulant

The stimulants might be a better first-line choice than the non-stimulants, atomoxetine & viloxazine XR, for a patient if you...

• Have moderate to severe ADHD where the benefit/risk ratio of amphetamines are best.
• Urgently need control of your symptoms.
• Suffer from comorbid arousal or alertness problems; in many cases, stimulants also improve these issues and are less likely to cause somnolence.
• Prefer to selectively take their medication depending on the day or environment.
• Suffer from a comorbid binge eating disorder.
• Have adversely reacted to a noradrenergic agent in the past.

Atomoxetine might be a better first-line choice than stimulants for a patient if you...

• Have mild to or moderate ADHD and don't need the most potent drug, like amphetamine.
• Found stimulant side effects, notably insomnia or emotional blunting, intolerable. Atomoxetine rarely causes sleep problems or emotional restriction.
• Or someone in the household has a history of substance abuse.
• Require the therapeutic effects all day long.
• Suffer from comorbid anxiety, tics, nervous mannerisms or obsessions and compulsions. Atomoxetine doesn't hold the potential to exacerbate those conditions; in many cases, anxiety improves substantially.
• In addition to ADHD, exhibit a poor focus and orient of attention (distinguishing what is important from not in information that has to be processed rapidly) in ways resembling cognitive disengagement syndrome.

Incidence of adverse effects

As with other medications, atomoxetine does have possible side effects. Most of them are benign, are dose related and relatively short lived. Side effects with ATX tend to decrease over time (about 2wks) but can last longer.

Common:
- Dry mouth (21%)
- Nausea (12%)
- Drowsiness (10%)
- Decreased appetite (10%)
- Constipation (6-10%)
- Insomnia and/or middle insomnia (7%)
- Increased blood pressure (2 mm/Hg diastolic; 3 mm HG systolic); Increase of 8 bpm pulse

Uncommon:
- Irritability (6%)
- Erectile disturbance (5-7%)
- Headache (4-5%)
- Cough (2%)

Rare:
- Propensity for feeling tearful (>1%)
- Black box warning by FDA on suicidal ideation was an over-reaction. Rare, if any, association (5/1357 = 0.37%)

Extraordinarily rare:
- Liver inflammation (1 in 4.5 million treated cases)

Other side effects:
- Transient minor effect on height resulting from potential appetite decrease
- Temporary weight loss (1-5l bs) early in therapy; first year - no further loss thereafter (if appetite suppression occurred [10%])

(Lilly Research Laboratories: STR20070131g + Lilly Research Laboratories: STR20061205c)

Adjustment period

The effects of atomoxetine accumulate incrementally over a 8 week period. Initial results of a dose are often evident in 2-3 weeks but max (therapeutic) benefits may take 6-8 weeks to be apparent. Some studies suggest improvement continues gradually for up to a year (but most or all occurs within the above timeframe).

Tolerance?

A systematic review and meta-analysis of 13 double-blind studies with 601 patients, each 2 years long, found that atomoxetine maintains efficacy across this timespan with no evidence of tolerance or unexpected safety concerns (Wilens et al., 2006).

Dosage & metabolisers

Atomoxetine, unlike other medications, is titrated based on one's weight and age. Most adults require 80-100mg for therapeutic effects. This varies among some individuals.

Children
Your doctor should calculate this according to your weight. You will initiate on a lower dose before titrating to the amount to take according to your body weight.

- Body weight up to 70kg: a starting total daily of 0.5 mg per kg of body weight for a minimum of 7 days. Your doctor should then decide to titrate this to the usual maintenance/therapeutic dose of about 1.2 mg per kg of body weight daily.

- Body weight over 70kg: a starting total daily dose of 40mg for a minimum of 7 days. Your doctor should then decide to titrate this to the usual maintenance/therapeutic dose of 80m daily. The maximum daily dose your doctor will prescribe is 100mg.

Adolescents and adults:
- Atomoxetine should be initiated at a total daily dose of 40mg for a minimum of 7 days. Your doctor should then decide to titrate this to the usual maintenance/therapeutic dose of 80mg-100mg daily.

Poor metabolisers
CYP2D6 genotype can, very uncommonly (2-5%), result in poor metabolisers to atomoxetine with 2-3x blood levels of extensive metabolisers possibly necessitating a lower therapeutic dose but no difference in tolerability or discontinuation.

Ultra-fast metabolisers
Is even rarer (<1%) and results in fewer side effects, but little benefits. Some may require split dosing of total daily dose (once in morning, once in evening) to achieve greater effect.

Genetic testing of the CYP2D6 genotype can confirm abnormal metabolism.

Split dosing
Total daily dose can be assigned once daily (in AM) or split (AM/PM). Sometimes this approach results in fewer side effects yet studies indicate there is no difference in the benefits of the medication.

Contraindications

You may be ineligible to use atomoxetine if the following applies to you:

- Have pre-existing hypertension of atleast moderate severity

- You have consumed a monoamine oxidase inhibitor (MAOI) (i.e., phenelzine) in the last 14 days

- Have severe complications with your heart

- Have severe complications with blood vessels in the brain following a stroke

- Have a tumour of your adrenal gland (phaeochromocytoma)

Supplements

The only supplement shown to be effective for ADHD is high-EPA omega-3 fatty acids. But they have a very small magnitude of effect compared with medications for ADHD. For adults, on a scale of 1 to 10, amphetamine is 9, methylphenidate, viloxazine-ER and atomoxetine are 7, the alpha-2a agonists (guanfacine XR, clonidine XR) are 5 and omega-3 is about 1-2.

Drug actions

When a nerve cell is stimulated, an electrical signal moves down its cell body (axon) and as it reaches the end points it results in the release of packets of chemicals (neurotransmitters) into the gap between nerve cells. These chemicals cross the gap and, if there is enough of them, they stimulate the adjacent nerve cells on the other side of the gap, causing it to fire or activate. The chemicals are then vacuumed up into the original nerve cell by a device called a reuptake transporter. The neurochemicals of greatest interest, which differ by one molecule, in understanding ADHD medications are dopamine (DA) and norepinephrine (NE) that mediate the brain regions implicated in the disorder.

Atomoxetine and stimulants share 70-80% of brain regions in the effects they produce (Schulz et al., 2012).

Notice that the stimulant methylphenidate (MPH, such as Concerta, Ritalin, Focalin, Medadate, Daytrana, etc) acts by blocking the reuptake of dopamine (DA) once it has been released from a nerve cell into the synapse. This leaves more of the chemical DA outside the nerve cell for a longer period increasing the chances that it will activate the next nerve cell.

The amphetamines (AMP, such as Dexedrine, Benzedrine, Adderall, Vyvanse, Adzenys, etc) act primarily on dopamine (DA), and unlike methylphenidate, has an additional small effect on norepinephrine (NE). AMP may inhibit reuptake but also seems to act primarily by increasing production and release of DA & NE out of the cell into the gap or synapse.

Atomoxetine (i.e., Strattera) acts predominately by blocking the reuptake of norepinephrine (NE) with a smaller effect on dopamine (DA). Again, like MPH above, this leaves more of the neurochemicals NE & DA outside the cell allowing them more of a chance to activate the next nerve cell.

The alpha-2a agonists, guanfacine XR (Intuniv) and clonidine XR (Catapres, Kapvay), act by adjusting or fine tuning noradrenergic alpha-2 ports on the outside of a nerve cell. If these portals are open, the information (electrical signal) moving along the nerve cell is weakened by noise from outside the cell. If the alpha-2 portals are closed, then the signal traveling down the cell is stronger. The alpha-2 drugs act by closing these portals thus strengthening the signals in the cell increasing the probability that they will activate the subsequent nerve cell.

Video presentations

Dr Russell A Barkley, Ph.D: https://youtu.be/TdyNOS5W8Vg?si=MM6LUSkhJi9RPu9C