Atomoxetine

Indications

• FDA-approved for attention-deficit/hyperactivity disorder in children age 6 years and older, adolescents, and adults as monotherapy.
• First-line non-stimulant when there is active substance misuse, diversion risk, or a patient or family preference against controlled substances.
• Preferred when stimulants worsen comorbid anxiety, tics, or insomnia, since atomoxetine does not aggravate these and covers 24 hours.
• Used off-label as an add-on to a stimulant for residual evening or early morning symptoms, though combination data remain limited.
• Used off-label for ADHD symptoms in adults with comorbid anxiety disorders, where trials show benefit for both symptom domains.
• Not effective for narcolepsy, binge eating disorder, or as an antidepressant, despite its noradrenergic mechanism.

Mechanism of action

• Selectively inhibits the presynaptic norepinephrine transporter, raising synaptic norepinephrine throughout cortical and subcortical circuits.
• In prefrontal cortex, where dopamine is largely cleared by the norepinephrine transporter, it also raises prefrontal dopamine.
• It does not increase dopamine in nucleus accumbens or striatum, which explains the absence of euphoria and abuse liability.
• Enhanced tonic prefrontal catecholamine signaling improves attention and impulse control gradually rather than dose by dose.
• Because the effect depends on receptor adaptation rather than acute release, benefit accrues over weeks and persists overnight.

Pharmacokinetics

• Rapidly absorbed with Tmax of 1-2 hours; food slows absorption modestly and reduces peak concentration, which can lessen nausea.
• Metabolized primarily by CYP2D6 to the equipotent 4-hydroxyatomoxetine, with CYP2C19 providing a minor pathway.
• Half-life is about 5 hours in extensive metabolizers but 22 hours in poor metabolizers, who have roughly tenfold higher exposure.
• Approximately 7 percent of White and 2 percent of Black patients are CYP2D6 poor metabolizers, a group with more adverse effects.
• Hepatic impairment increases exposure substantially, requiring a 50 percent dose reduction in Child-Pugh B and 75 percent in Child-Pugh C.

Dosing

• Children and adolescents up to 70 kg: start 0.5 mg/kg/day PO, increase after at least 3 days to a target of about 1.2 mg/kg/day.
• Maximum in patients up to 70 kg is 1.4 mg/kg/day or 100 mg/day, whichever is less, given once in the morning or split twice daily.
• Adults and patients over 70 kg: start 40 mg/day, increase after at least 3 days to 80 mg/day, with a maximum of 100 mg/day.
• Known CYP2D6 poor metabolizers and patients on strong CYP2D6 inhibitors should start at 0.5 mg/kg/day and increase only after 4 weeks.
• Hepatic impairment: reduce to 50 percent of the usual dose in Child-Pugh class B and to 25 percent in Child-Pugh class C.
• No taper is needed on discontinuation, and no rebound hyperactivity or withdrawal syndrome occurs when it is stopped.

Adverse effects

• Nausea, decreased appetite, dry mouth, fatigue, insomnia, and dizziness are the common effects and often improve after the first few weeks.
• Adults report urinary hesitancy or retention, erectile dysfunction, and dysmenorrhea more often than children do.
• Small mean rises in heart rate of about 5-10 bpm and in blood pressure of 2-4 mmHg, with orthostatic hypotension and syncope reported.
• Severe hepatic injury is rare but real, presenting as jaundice, dark urine, or transaminase elevation and requiring permanent discontinuation.
• Priapism has been reported in children and adults, and any erection lasting over 4 hours needs urgent evaluation.
• Growth in children slows early, with weight and height typically returning toward baseline percentiles over 2-3 years of treatment.

Monitoring

• Baseline and periodic height, weight, blood pressure, and pulse, including orthostatic vitals in patients reporting dizziness.
• Ask about suicidal thoughts, agitation, irritability, and unusual behavior at every visit in the first months, especially in youth.
• Liver chemistry is not required routinely, but obtain transaminases and bilirubin promptly for jaundice, dark urine, or right upper quadrant pain.
• Use a validated rating scale at baseline and at 4 and 8 weeks, because a fair trial takes at least 6 weeks at target dose.
• Consider CYP2D6 genotyping when adverse effects appear at low dose or when there is no response at maximal dose.

Interactions

• Contraindicated within 14 days of an MAOI because of the risk of serious, sometimes fatal, hypertensive and hyperthermic reactions.
• Strong CYP2D6 inhibitors such as paroxetine, fluoxetine, bupropion, and quinidine raise exposure several-fold, so titrate slowly and cap the dose.
• Contraindicated in narrow-angle glaucoma, pheochromocytoma, and severe cardiovascular disease including serious structural cardiac abnormality.
• Pressor agents including albuterol and decongestants can produce additive increases in blood pressure and heart rate.
• Additive cardiovascular effects with stimulants and with drugs that prolong the QT interval warrant closer vital sign monitoring.

Special populations

• Pregnancy: human data are limited and no clear teratogenic pattern is known; use only when the benefit justifies the potential fetal risk.
• Lactation: minimal published data on transfer into human milk, so monitor the breastfed infant for irritability and poor feeding.
• Pediatric: approved from age 6 years; the suicidality boxed warning applies specifically to children and adolescents.
• Geriatric: safety and effectiveness have not been established in patients over 65, and orthostatic effects are more consequential.
• Hepatic impairment requires substantial dose reduction, while renal impairment does not require dose adjustment.

Clinical pearls

• It is not a rescue drug; judge it at 6 weeks on target dose, not at week 1.
• Fluoxetine or paroxetine turns almost any patient into a CYP2D6 poor metabolizer; start low.
• Dosing at night with food often solves both the nausea and the sedation complaints.