Atomoxetine


Atomoxetine, sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor medication used to treat attention deficit hyperactivity disorder and, to a lesser extent, cognitive disengagement syndrome. It may be used alone or along with psychostimulant medication. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.
Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. There is a lack of data regarding its safety during pregnancy; as of 2019, its safety during pregnancy and for use during breastfeeding is not certain.
It was approved for medical use in the United States in 2002. In 2023, it was the 161st most commonly prescribed medication in the United States, with more than 3million prescriptions.

Medical uses

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder

Atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. One of the primary differences with the standard stimulant treatments for ADHD is that it has little known abuse potential. Meta-analyses and systematic reviews have found that atomoxetine has comparable efficacy and equal tolerability to methylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent.
While its efficacy may be less than that of lisdexamfetamine, there is some evidence supporting its use in combination with stimulants. Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; in combination with a stimulant to increase effectiveness; when the cost of stimulants is prohibitive; or when there is concern about the abuse potential of stimulants in a patient with a history of substance use disorder.
Atomoxetine alleviates ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine in the prefrontal cortex, sharing 70–80% of the brain regions with stimulants in its produced effects.
Unlike α2-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal symptoms being observed.
The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. Incrementally increasing response may occur up to 1 year or longer. The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.

Other uses

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome, as multiple randomised controlled clinical trials have found that it is an effective treatment. In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.

Traumatic brain injury

Atomoxetine is sometimes used in the treatment of cognitive impairment and frontal lobe symptoms due to conditions like traumatic brain injury. It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition, lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome. A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects. Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.

Contraindications

include:
Common side effects include abdominal pain, decreased appetite, nausea, erectile dysfunction, feeling tired, dizziness and urinary retention. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. A 2020 meta-analysis found that atomoxetine was associated with anorexia, weight loss, and hypertension, rating it as a "potentially least preferred agent based on safety" for treating ADHD. As of 2019, safety in pregnancy and breastfeeding is not clear; a 2018 review stated that, "because of lack of data, the treating
physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy."
The U.S. Food and Drug Administration has issued a black box warning for suicidal behavior/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects upon abrupt discontinuation.

Overdose

Atomoxetine can lead to cardiac complications, with severe overdose requiring intensive medical care to avoid death.

Interactions

Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.
Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM, which has the potential to cause arrhythmia. QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolizers.
Other notable drug interactions include:
Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.

Pharmacology

Pharmacodynamics

Atomoxetine inhibits the presynaptic norepinephrine transporter, preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter expression is minimal. In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree. In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.
Atomoxetine's status as a serotonin transporter inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively. However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment. Supporting atomoxetine's selectivity, a human study found no effects on platelet serotonin uptake and inhibition of the pressor effects of tyramine.
Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations. It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site. Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D1 or α1-adrenergic receptor antagonists, but could be potentiated by NMDA or an α2-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels. Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.
Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors. Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers. It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.
4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.