Non-Stimulants for ADHD

Atomoxetine is a potent selective inhibitor of the presynaptic NE transporter.  It increases norepinephrine at the synapse.

Atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). 

Initial responses to atomoxetine may be apparent within 1 week of treatment but can take longer (median 23 days in a 6-week study: n=72). Responses often build gradually over time and may not be robust until after 3 months. 

A pooled analysis of six randomized placebo-controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [≥40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6-9 weeks.

Indications 

Atomoxetine is FDA-indicated for the treatment of ADHD in patients down to 6 years of age.  

Dosing Strategies

Atomoxetine dosing is weight-based, with an initial target dose of 1.2 mg/kg/day and range up to 1.8 mg/kg/day.  

The dose must be titrated up gradually to avoid distressing GI side effects.

The starting dose is about 0.3 mg/kg/day for 7 days.

Atomoxetine may be prescribed in divided doses (bid) if needed to increase tolerability.

Adverse Effects

Common: somnolence, anorexia, small increase in blood pressure and pulse; minimal QTc prolongation

Rare: 

Hepatic injury has been reported and related to atomoxetine in at 3 cases, one requiring transplant.

Suicidality – the FDA added the boxed warning on suicidality to atomoxetine.  In one pooled analysis, the risk of suicidal ideation in patients treated with atomoxetine was 5/1,357 patients vs. none with placebo.  In another analysis there was no difference in suicidality between atomoxetine and placebo.

Monitoring or Tests

No laboratory tests are needed

Monitor height, weight, blood pressure and pulse

Drug Interactions

Atomoxetine is metabolized by CYP2D6.  Poor CYP2D6 metabolizers, and those taking medications which inhibit CYP2D6 (such as fluoxetine or quinidine) will need lower doses of atomoxetine.

Course of treatment

Although there are no trials of atomoxetine longer than 3 years, practically speaking it can be used indefinitely.  Once at a therapeutic dose, adjustments can be made to allow for growth, keeping the dose in the 1.2 to 1.8 mg/kg/day range.

Discontinuation

There is no documented discontinuation syndrome and no need to taper off.

Viloxazine

Viloxazine extended-release (Qelbree) is an norepinephrine reuptake inhibitor approved for the treatment of ADHD in children aged 6-17 in 2021.  FDA approval was extended to the treatment of ADHD in adults in 2022.  

Viloxazine extended-release is a once-daily capsule that can be opened and the contents sprinkled on a spoonful of applesauce.

Viloxazine extended-release comes in 100, 150, and 200 mg capsules.  Recommended dosing starts at 100 mg daily for children aged 6-11 years and 200 mg daily for adolescents.  Dose is titrated to effect with a maximum of 400 mg/day.  

Common adverse effects associated with viloxazine extended-release are somnolence, insomnia, decreased appetite, fatigue, headache, nausea, dry mouth and constipation.  

The alpha agonists used in the treatment of ADHD include the extended-release forms of guanfacine and clonidine.  

Alpha agonists have been used for years in children in their immediate-release forms, mostly for hyperactive or disruptive behavior in younger children.

Utility of the immediate release forms has been limited by sedating effect and limited duration of action per dose (about 4 hours).

Indications and Evidence Base

Extended-release forms of alpha agonists were FDA approved for ADHD in children aged 6-17 years

Guanfacine ER (Intuniv) was approved in 2009.

Clonidine ER (Kapvay) was approved in 2010.

Both are approved for use as monotherapy for ADHD or as augmentation therapy with a stimulant.

The alpha agonists are less effective than are stimulants in the treatment of pediatric ADHD.

Dosing Strategies – Extended-release alpha agonists

Take 2-4 weeks for full effect. 

Once effective provide 24-hour coverage. 

Tablets must be swallowed whole for sustained release

guanfacine ER: 

•1 mg daily increasing by 1 mg/week to max 0.12 mg/kg/day or 4 mg/day (6-12 years) or 7 mg/day (13-17 years)

•Originally maximum dose was 4 mg day but doses up to 7 mg in adolescents are tolerated and effective.

clonidine ER: 

•Start with 0.1 mg q bedtime, increase by 0.1 mg/week to max of 0.2 mg bid

• Must be given bid for 24-hour effect.

Dosing Strategies –Immediate-release alpha agonists

Moderately effective for inattention, hyperactivity, impulsivity and tics. Nighttime dose helps with sleep onset, may be higher than daytime doses.

Each immediate-release dose lasts 4-6 hours.

guanfacine: 

• patient weight <45 kg: 0.5 mg nightly, titrate in 0.5 mg increments TID to max daily dose 2 mg (27-40.5 kg) or 3 mg (40.5-45 kg).  

•patient weight >45 kg: 1 mg nightly, titrate in 0.5 mg increments TID to max dose 4 mg/day.

clonidine: 

• patient weight <45 kg: 0.05 mg nightly, titrate in 0.05 mg increments QID to max dose 0.2 mg (27-40.5 kg) or 0.3 mg (40.5-45 kg).  

• patient weight >45 kg: 0.1 mg nightly, titrate in 0.05 mg increments QID to max dose 0.4 mg/day.

Adverse Effects

All alpha agonists may cause sedation, somnolence and fatigue which may decrease over time.  Extended-release forms are associated with less sedation than are immediate-release forms.

Alpha agonists reduce pulse and blood pressure and rebound hypertension may occur after abrupt discontinuation.

Pulse and blood pressure reductions with guanfacine ER run about 3-4 beats per minute and 1-2 mm Hg for both systolic and diastolic pressures. 

Syncope is a rare side effect.

Monitoring or Tests

Monitor blood pressure, particularly with immediate-release forms

Drug Interactions

Guanfacine is mainly metabolized by CYP3A4.  The package insert recommends that in patients taking guanfacine, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved.

There are no significant known CYP450 interactions with clonidine.  

Use with caution with other agents that lower blood pressure.

Course of treatment

The alpha agonists are rarely first-line treatment for ADHD.  Monotherapy with alpha agonists may be considered if a patient cannot take a stimulant due to adverse effects or a medical condition.  Alpha agonists may be appropriate first-line treatment for ADHD symptoms in patients with Autism Spectrum Disorder.  

When used as augmentation to stimulant medication, look for overall improvement in ADHD symptoms during the day when the stimulant is effective, as well as decreased symptoms in the early morning and the evenings when the stimulant effect is absent.  

Use parent and teacher rating scales to guide treatment decisions.

If using as augmentation, re-assess the treatment plan every year or 2.  Is combination therapy still necessary?  To test the contribution of the alpha, begin a slow taper off and monitor for return of symptoms.  If this occurs, simply go back to the effective dose.  

Discontinuation

Taper off to avoid rebound hypertension.

Check out the following modules for more information on ADHD medication management:

When to Use a Non-stimulant Medication for ADHD  (Mini-lesson)