What is atomoxetine and how is it used to treat Attention Deficit Hyperactivity Disorder (ADHD)?

Atomoxetine: Comprehensive Clinical Guide

What Atomoxetine Is

Atomoxetine is a selective norepinephrine reuptake inhibitor FDA-approved for treating ADHD in children (≥6 years), adolescents, and adults—it is the first non-stimulant medication approved for ADHD and remains the only agent with FDA approval for adult ADHD. 1, 2

• Atomoxetine works by binding to the norepinephrine transporter, increasing synaptic noradrenaline throughout the brain 3
• In the prefrontal cortex specifically, where dopamine transporters are scarce, atomoxetine also increases dopamine levels by blocking norepinephrine transporters that regulate dopamine reuptake 3
• This mechanism differs fundamentally from stimulants, providing continuous "around-the-clock" symptom control without the peaks and valleys of stimulant medications 4

Position in Treatment Algorithm

Stimulants remain first-line therapy for ADHD due to larger effect sizes, with atomoxetine positioned as second-line treatment in most guidelines. 3, 4

When to Consider Atomoxetine First-Line:

• Patients with comorbid substance use disorders (no abuse potential) 4, 5
• Patients with tic disorders or Tourette's syndrome 4
• Patients experiencing significant sleep disturbances on stimulants 4
• Patients or families who refuse controlled substances 5
• Patients with comorbid anxiety disorders 5

Evidence for Efficacy:

• Elementary school-aged children (6-11 years): Evidence is "sufficient but less strong" than stimulants 3
• Adolescents (12-18 years): FDA-approved with strong recommendation for use 3, 4
• Adults: Only ADHD medication with original FDA approval for adult treatment 2, 6

Dosing and Administration

Start atomoxetine at 0.5 mg/kg/day for children/adolescents up to 70 kg (or 40 mg/day for those >70 kg and adults), titrate to target dose of 1.2 mg/kg/day with maximum of 1.4 mg/kg/day or 100 mg/day, whichever is lower. 4

Titration Schedule:

• Increase dose every 7-14 days based on tolerability 4
• Can be given as single morning dose, single evening dose, or split into two evenly divided doses 4, 7
• Split dosing may reduce side effects, particularly initial somnolence and gastrointestinal symptoms 4, 8

Formulations Available:

• Capsules: 10,18,25,40,60,80, or 100 mg 3
• Oral solution: 4 mg/mL 3
• Do not chew, crush, or open capsules 1

Critical Metabolism Consideration:

• Atomoxetine is metabolized primarily through CYP2D6 3, 4
• Approximately 7% of the population are poor CYP2D6 metabolizers with significantly higher plasma levels and increased adverse effects 8
• Dose adjustments needed when used with CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) which can elevate serum atomoxetine levels 3, 4

Timeline for Therapeutic Effect

Atomoxetine has a delayed onset requiring 6-12 weeks to achieve full therapeutic effect—this is fundamentally different from stimulants which work within hours. 4, 8

• Assess treatment response only after 6-12 weeks, not earlier 4
• Patients and families must be counseled about this delay to prevent premature discontinuation 4
• Some symptom improvement may occur earlier, but maximum benefit takes months 7

Critical Safety Warnings

BLACK BOX WARNING: Suicidal Ideation

The FDA mandates close monitoring for suicidal ideation in children and adolescents, especially during the first few months of treatment or with dose changes. 3, 4, 1

• Analysis of 12 placebo-controlled trials showed 4 out of 1,000 pediatric patients developed suicidal thoughts (vs. placebo) 1
• This risk was NOT observed in adult trials 3, 8
• Monitor for: anxiety, agitation, panic attacks, irritability, hostility, aggressiveness, impulsivity, restlessness, mania, depression 1
• Do not assume mood changes will spontaneously resolve—they require immediate clinical evaluation 8

Severe Liver Injury Warning

Atomoxetine can cause severe liver injury; discontinue immediately if jaundice or laboratory evidence of liver injury develops. 3, 1

• Monitor for: itching, right upper abdominal pain, dark urine, yellow skin/eyes, unexplained flu-like symptoms 1
• Three postmarketing cases of serious liver injury deemed probably related to atomoxetine 5
• Extremely rare but potentially life-threatening 3

Cardiovascular Warnings

Obtain personal and family cardiac history before starting atomoxetine; consider ECG if risk factors present. 3

• Atomoxetine causes mild increases in heart rate and blood pressure 3, 9
• Risk of sudden death in patients with structural cardiac abnormalities 1
• Risk of stroke and heart attack in adults 1
• Monitor blood pressure and heart rate regularly during treatment 3, 4
• Contraindicated in patients with pheochromocytoma 1

Psychiatric Warnings

Screen for bipolar disorder before initiating atomoxetine; monitor for emergent psychotic or manic symptoms. 3, 1

• Can precipitate mixed/manic episodes in patients with comorbid bipolar disorder 3
• New psychotic symptoms (hallucinations, delusions) or manic symptoms require immediate evaluation 1
• May cause aggressive behavior or hostility 3, 1

Other Important Warnings:

• Narrow-angle glaucoma is a contraindication 1
• Can cause urinary retention/hesitation 3
• Rare cases of priapism reported 3
• Rebound hypertension possible with abrupt discontinuation (though less concern than with alpha-2 agonists) 3

Common Adverse Effects

In Children and Adolescents:

• Decreased appetite (most common) 3, 4, 6
• Nausea and vomiting 3, 4
• Abdominal pain 3, 5
• Fatigue and somnolence (especially initially) 3
• Headache 4, 5
• Irritability 3, 8

In Adults:

• Dry mouth 9, 5
• Insomnia 9
• Nausea 9, 5
• Decreased appetite 9
• Constipation 9
• Urinary retention or hesitation 9
• Sexual dysfunction (~2% of patients): erectile disturbance, decreased libido, dysmenorrhea 9, 5
• Dizziness 9, 5

Managing Side Effects:

• Initial somnolence and GI symptoms worsen if dose increased too rapidly—slow titration prevents this 3, 8
• Consider split dosing (morning and evening) to reduce side effects 4, 8
• If evening dose causes insomnia, shift to morning-only dosing 4
• Discontinuation rate in trials: 3.5% (atomoxetine) vs. 1.4% (placebo), higher at doses >1.5 mg/kg/day 9

Growth Effects

Atomoxetine causes initial delays in expected height and weight trajectories during the first 1-2 years, with return to expected measurements after 2-3 years of treatment. 3

• Decreases most pronounced in children who were taller or heavier than average before treatment 3
• Less impact on growth compared to stimulants 4
• Monitor growth parameters regularly 4

Drug Interactions

Major Interactions:

• Contraindicated with MAOIs or within 14 days of MAOI discontinuation 1
• CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, quinidine) significantly increase atomoxetine levels 3, 4
• Albuterol or other beta-2 agonists: use with caution due to cardiovascular effects 1
• Pressor agents: atomoxetine may potentiate cardiovascular effects 1

Medications Requiring Caution:

• Antihypertensives: monitor blood pressure closely 1
• Other medications affecting blood pressure or heart rate 1

Special Populations

Preschool Children (4-5 years):

• No nonstimulant medication, including atomoxetine, has sufficient evidence for use in preschool-aged children 3
• Methylphenidate is preferred if medication needed in this age group 3

Patients with Hepatic Impairment:

• Dose reduction required due to increased atomoxetine exposure 5
• Moderate hepatic insufficiency: reduce to 50% of normal dose 5
• Severe hepatic insufficiency: reduce to 25% of normal dose 5

Pregnancy and Breastfeeding:

• Pregnancy Category C: unknown if atomoxetine harms unborn baby 1
• Pregnancy registry available: 1-866-961-2388 or https://womensmentalhealth.org/adhdmedications/ 1
• Unknown if atomoxetine passes into breast milk—discuss risks/benefits 1

CYP2D6 Poor Metabolizers:

• Approximately 7% of Caucasians, 2% of African Americans, <1% of Asians 8
• Experience 10-fold higher plasma concentrations and 5-fold longer half-life 8
• Increased risk of adverse effects, particularly cardiovascular and mood-related 8
• Consider dose reduction or more gradual titration 4

Advantages Over Stimulants

• No abuse potential—not a controlled substance 4, 5, 6
• Continuous 24-hour symptom coverage without rebound 4, 5
• Can be dosed once daily (morning or evening) for flexibility 4, 7
• May improve comorbid anxiety symptoms 5
• Does not exacerbate tics 4
• Less likely to cause insomnia compared to stimulants 5
• May be better tolerated in patients with comorbid autism spectrum disorder 4

Disadvantages Compared to Stimulants

• Smaller effect size than stimulants 3, 4
• Delayed onset of 6-12 weeks vs. hours for stimulants 4, 8
• Less effective than extended-release methylphenidate (OROS) and extended-release mixed amphetamine salts in head-to-head trials 5
• Similar or noninferior to immediate-release methylphenidate only 5

Monitoring Requirements

Initial Assessment:

• Personal and family cardiac history 3
• Screen for bipolar disorder, psychosis, suicidal ideation 1
• Baseline blood pressure and heart rate 3, 4
• Baseline height and weight 3
• Assess for narrow-angle glaucoma 1
• Assess for pheochromocytoma 1

Ongoing Monitoring:

• Blood pressure and heart rate at each visit 3, 4
• Height and weight regularly 3, 4
• Close monitoring for suicidal ideation, especially first few months and with dose changes 3, 4, 1
• Monitor for mood changes, irritability, aggression, psychotic symptoms 8, 1
• Assess for liver injury symptoms 1
• Evaluate ADHD symptom response after 6-12 weeks 4

Periodic Reassessment:

• Consider medication-free intervals periodically to determine continued need for treatment 3
• Reassess diagnosis and treatment plan regularly 3

Adjunctive Therapy

Extended-release guanfacine and extended-release clonidine are the only medications with FDA approval for adjunctive use with stimulants; atomoxetine has limited evidence for combination therapy. 3

• Some limited evidence supports combining atomoxetine with stimulants for augmentation 3
• This remains off-label use 3
• Consider if stimulant monotherapy provides insufficient response 3

When to Discontinue or Switch

Discontinue Atomoxetine If:

• Suicidal ideation emerges 8, 1
• Signs of liver injury develop 1
• Severe cardiovascular symptoms occur 1
• Psychotic or manic symptoms emerge 1
• Inadequate response after 6-12 week trial at optimal dose 4
• Intolerable side effects persist despite dose adjustment 8

Alternative Options:

• Trial of stimulant medication (methylphenidate or amphetamine) if atomoxetine ineffective 4
• Extended-release guanfacine or clonidine as alternative non-stimulants 3, 4
• Combination therapy with behavioral interventions 3

Key Clinical Pearls

• Atomoxetine requires patience—counsel families about 6-12 week timeline before judging efficacy 4, 8
• Never ignore new mood changes or assume they will resolve spontaneously 8
• Split dosing can significantly improve tolerability during titration 4, 8
• Slow titration prevents most GI side effects and somnolence 3, 8
• Check for CYP2D6 inhibitor co-medications before prescribing 3, 4
• Atomoxetine is particularly valuable for patients with substance abuse risk or those refusing controlled substances 4, 5
• Evening dosing may benefit college students who need coverage for evening studying 4
• Discontinuation is generally well-tolerated without rebound symptoms 5
• The black box warning for suicidal ideation applies only to pediatric patients, not adults 3, 8