Atomoxetine

Attention deficit hyperactivity disorder

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).^[6] It is approved for use in children, adolescents, and adults.^[6] However, its efficacy has not been studied in children under six years old.^[9] One of the primary differences with the standard stimulant treatments for ADHD is that it has no known misuse potential.^[9][32] 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.^{[23][24][25][26]} The benefits of atomoxetine against ADHD symptoms are dose-dependent until a plateau is reached.^[33]

While its efficacy may be less than that of lisdexamfetamine,^[34] there is some evidence supporting its use in combination with stimulants.^[18] 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;^[35][36] when the cost of stimulants is prohibitive; or when there is concern about the misuse potential of stimulants in a patient with a history of substance use disorder.

Atomoxetine, similarly to stimulants, appears to reduce emotional lability associated with ADHD in adults.^[37]

Atomoxetine is thought to alleviate ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine levels in the prefrontal cortex,^[38] sharing 70–80% of the brain regions with stimulants in its produced effects.^[39]

The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent.^[8][40][41] A further 2 to 4 weeks may be required for the full therapeutic effects to be seen.^[42][40] Incrementally increasing response may occur up to 1 year or longer.^[41][43] The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.^[6]

Other uses

Available forms

Atomoxetine is available in the form of oral capsules (10, 18, 25, 40, 60, 80, or 100 mg) and in an oral solution (4 mg/mL).^[62][63] It is taken once or twice daily.^[2][3]

Pharmacodynamics

Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), 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 (DAT) expression is minimal.^[11] 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 (DRI), was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.^[95][94] In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.^[96] Atomoxetine is selective for the NET over many other targets.^[3][97][98]

Atomoxetine's status as a serotonin transporter (SERT) 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.^[99] 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.^[94][96] Supporting atomoxetine's selectivity, human studies found no effects on platelet serotonin uptake (a marker of SERT inhibition) but robust inhibition of the pressor effects of tyramine (a marker of NET inhibition).^[100][101] Subsequently, atomoxetine was found to dose-dependently inhibit the NET from low doses in humans but did not inhibit the SERT to a clinically significant degree.^[101][102] Conversely, venlafaxine robustly inhibited the SERT but only inhibited the NET at high doses.^[101]

Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations (IC₅₀Tooltip half-maximal inhibitory concentration = ~3,000 nM).^[103][104] It causes a use-dependent open-channel block and its binding site overlaps with the Mg²⁺ binding site.^[103][104] 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.^[105] In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels.^[106] Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.^[107][108]

Atomoxetine also reversibly inhibits G protein-coupled inwardly rectifying potassium channel (GIRK) currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner.^[109] K_ir3.1/3.2 ion channels are opened downstream of M₂, α₂, D₂, and A₁ stimulation, as well as other G_i-coupled receptors.^[109] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.^[109] It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

It has been found to inhibit voltage-gated sodium channels.^[110][111]

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 the μ-opioid receptor (MOR) and as a partial agonist at the κ-opioid receptor (KOR).^[93] The affinities (IC₅₀Tooltip half-maximal inhibitory concentration) of 4-hydroxyatomoxetine were 164 nM for the MOR, 88 nM for the KOR, 1,490 nM for the δ-opioid receptor (DOR), and >5,000 nM for the nociceptin receptor (ORL-1).^[93] Atomoxetine itself showed dramatically lower affinities (e.g., 25- to 50-fold).^[93] It is not known whether the actions of 4-hydroxyatomoxetine at the opioid receptors leads to CNS-related adverse effects with atomoxetine.^[93]

Atomoxetine does not alter locomotor activity in rodents, in contrast to stimulants like amphetamine.^[32] In addition, atomoxetine does not produce self-administration in monkeys, also in contrast to stimulants like amphetamine.^[32] The drug does not produce stimulant-like effects, euphoria, or reinforcing effects in humans, instead increasing negative and unpleasant ratings at the highest assessed doses.^[32]

Atomoxetine has been found to increase cortisol levels in humans.^{[112][113][114]}

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed.^[11] First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers.^[11] Maximum plasma concentration is reached in 1–2 hours.^[11] If taken with food, the maximum plasma concentration decreases by 10–40% and delays the t_max by 3 hours.^[11] Drugs affecting gastric pH have no effect on oral bioavailability.^[6]

Following intravenous delivery, atomoxetine has a volume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells.^[11][115] It is highly bound to plasma proteins (98.7%), mainly albumin, along with α₁-acid glycoprotein (77%) and IgG (15%).^[11][87] Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.^[11]

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours.^[11][12] As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.^[12] Among CYP2D6 extensive metabolizers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9 hours.^[11][116] By contrast, among CYP2D6 poor metabolizers the half-life of atomoxetine averaged 20.0 hours and the half-life of N-desmethylatomoxetine averaged 33.3 hours.^[11][116] Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, with trough plasma concentrations (C_trough) residing around 30–40 ng/mL; however, both the time to steady-state levels and C_trough are expected to vary based on a patient's CYP2D6 profile.^[11][117]

Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L.^{[citation needed]} Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1% and 5% that of atomoxetine in CYP2D6 extensive metabolizers, and 0.1% and 45% that of atomoxetine in CYP2D6 poor metabolizers, respectively.^[6]

Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolizers, with >96% and 80% of a total dose being excreted in urine, respectively.^[11] The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolizers, but only 40% in poor metabolizers.^[11] CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.^[11]

Synthesis

Detection in biological fluids

Atomoxetine may be quantitated in plasma, serum, or whole blood to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage.^[120]

Names

Atomoxetine was originally known as tomoxetine. It was renamed to avoid medication errors, as the name may be confused with tamoxifen.^[126]

In India, atomoxetine is sold under brand names including Axetra, Axepta, Attera, Tomoxetin, and Attentin. In Australia, Canada, Italy, Portugal, Romania, Spain, Switzerland, and the US, atomoxetine is sold under the brand name Strattera. In France, hospitals dispense atomoxetine under the brand name Strattera (it is not marketed in France). In the Czech Republic, it is sold under brand names including Mylan. In Poland, it is sold under the brand name Auroxetyn. In Indonesia, it is sold under the brand name Xenocy. In Iran, atomoxetine is sold under brand names including Stramox. In Brazil, it is sold under the brand name Atentah. In Turkey, it is sold under the brand names Attex, Setinox, and Atominex. In 2017, a generic version was approved in the United States.^[125]

Legal status

Atomoxetine has no risk of misuse and is not a controlled substance.^[32][3]