Non-Stimulant Medications

Atomoxetine has been approved by the FDA for the treatment of ADHD in both children and adults; however, it may be less effective than stimulant medications. Atomoxetine is a noradrenergic reuptake inhibitor, and it has several important differences in comparison to stimulants. Atomoxetine has different side effects than stimulant medication and is more likely to cause sedation and nausea. The treatment effect may be smaller than that observed with stimulant medications, and its effect may take longer to appear.

Atomoxetine should be discontinued if symptoms of hepatic disease appear. This medication also carries cardiac warnings similar to stimulants. Lastly, atomoxetine carries a black box warning for suicidal ideation in children with ADHD, especially in the first month of treatment.

Clonidine has been evaluated for the treatment for ADHD in children with co-existing conditions, especially sleep disturbance. In a double-blind, randomized, placebo-controlled study of 122 children given clonidine, methylphenidate, or both, the authors concluded that methylphenidate offered a better combination of efficacy and tolerability compared to clonidine. Clonidine was efficacious but was also associated with increased sedation.

In 2010, extended-release clonidine was FDA approved for use alone or in conjunction with stimulant therapy for pediatric ADHD. The recommended initial dose is 0.1 mg at bedtime for children 6 years of age or older. The dose is then increased by 0.1 mg every week until the desired response is achieved, to a maximum of 0.4 mg per day. It should also be tapered down slowly upon discontinuation .

After being used for many years off label, extended-release guanfacine was approved for the treatment of ADHD in children and adolescents in 2009, either as monotherapy or an adjunct to stimulants. Guanfacine is an alpha-2A adrenergic agonist and acts by enhancing prefrontal cortical regulation of attention and impulse control.

In a multicenter, double-blind, placebo-controlled, fixed-dosage escalation study involving 345 patients 6 to 17 years of age, three dosages of guanfacine (2 mg, 3 mg, or 4 mg per day) were associated with significant improvements on hyperactivity/impulsivity and inattentiveness subscales compared to placebo . Additional studies have indicated that it may be particularly useful in children with ADHD and oppositional symptoms.

The recommended dose of guanfacine is 1 mg once daily; the dose may be adjusted by increments no larger than 1 mg/week, as tolerated, to a maximum dose of 4 mg/day. The most common adverse effects are somnolence, xerostomia, headache, fatigue, and sedation, but they are generally mild to moderate and/or transient.

Other non-stimulant drugs, including bupropion and tricyclic antidepressants, have been used to treat ADHD. However, there is limited evidence to support their use, and they have not received indications from the FDA for ADHD. The AACAP recommends clinicians consider using behavior therapy before using these agents because the level of effect may be similar.

Although bupropion does not have FDA approval for ADHD, it is considered by many to be a second-line agent for ADHD and possibly a first-line agent for patients who have both ADHD and either a mood disorder or a substance abuse disorder. Studies suggest that bupropion is effective and well tolerated in children and adolescents with ADHD and may have some efficacy in treating children with ADHD and conduct disorder (CD).

Small trials and one systematic review have also supported the use of bupropion for ADHD in adults, but more research is needed to determine its benefit and long-term outcomes in this population. However, more research is needed to establish the most appropriate role for this medication in the adult population.

Tricyclic Antidepressants
Certain tricyclic antidepressants, in particular desipramine, appear to have some efficacy in treating ADHD in children and adults [68,69]. However, there were reports of four children who had sudden death while being treated with desipramine, which led to a contraindication of its use in children younger than 12 years of age.

If tricyclic antidepressants are to be tried, a baseline ECG and ongoing monitoring are needed. These medications also carry warnings, including a boxed warning about suicide risk in children, adolescents, and young adults with depression. The use of desipramine for ADHD is off-label and should be reserved for cases where other medications have not been effective or were not tolerated.

Modafinil is a non-stimulant alertness agent initially approved for the treatment of narcolepsy and is currently not FDA approved in children or for ADHD. Concerns about serious skin rash and preliminary safety data have limited its use in children with ADHD.

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