04. Nonstimulant Treatments for ADHD

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Hi! David Rosenberg here for the Psychopharmacology Institute. In this Smart Take, we will look at nonstimulant treatments for ADHD. Newcorn and colleagues do an excellent job of articulating the pros and cons, some theoretical conclusions or potential for certain medicines, and certain areas where a particular medicine may be especially beneficial for a particular patient with ADHD. So, to review, 4 nonstimulant medications have FDA approval for ADHD. The norepinephrine reuptake inhibitor atomoxetine was the first nonstimulant to be approved.

Viloxazine extended release is also now FDA approved. The other options are alpha-2 long-acting adrenergic agents: Clonidine extended release and guanfacine extended release. There is a significant role for nonstimulants, especially when patients cannot tolerate stimulants, comorbidity is present, or parents and patients prefer nonstimulants or are unwilling to take the “Ritalin-type drugs.” There is also a significant role for nonstimulants as adjuncts in patients treated with stimulants. This is important because up to 30% of patients do not respond to stimulants or have inadequate and incomplete responses to stimulants. FDA-approved nonstimulants have moderate effect sizes but appear to be lower than stimulants. Moreover, this is not the case for all patients, but on average, the effect sizes are not quite as large as for stimulants. However, there are exciting parts of nonstimulants. One of which is that, overall, the duration of action of nonstimulants is generally longer than stimulants. Nonstimulants have a role in monotherapy and in combination with stimulants. In fact, that is often a way to get the best response in patients with ADHD, and in some cases, the combination of stimulants and nonstimultans limits the side effects of both. So, combining stimulants and nonstimulants may result in fewer side effects than when either is used alone. There seem to be certain situations where some nonstimulants may have a potentially more significant role.

Atomoxetine appears to be especially effective in treating ADHD patients with comorbid anxiety, and it is especially attractive because it increases the opportunity for monodrug therapy. That is for ADHD with anxiety; if a stimulant is used, you would have to use another medicine, such as an SSRI, and the same with most other treatments. However, atomoxetine allows you to use 1 medicine to take care of both symptoms. Now, the alpha-2 agonists—extended-release guanfacine and extended-release clonidine—are known to improve both hyperactivity, impulsivity, and inattention symptoms and are perfect choices for hyperarousal, aggression, tics, and insomnia, which can either be separate and distinct comorbidities with ADHD or in some cases may emerge with treatment with stimulants. Moreover, as I mentioned, alpha-2 agonists are excellent adjuncts when an incomplete response to stimulants or side effects preclude increasing the stimulant to the higher target doses. So, alpha-2 agonists have a significant role in ADHD. Viloxazine extended release has antidepressant activity and a longer half-life than atomoxetine, which may appeal to patients with ADHD and combined depression.

Now, there are some off-label options. Bupropion may be particularly helpful for ADHD when there is comorbidity with mood disorders, substance use disorders, and conduct disorder. Interestingly, the FDA has approved bupropion for smoking cessation, which is relevant given the high association between nicotine addiction in ADHD. Other exciting options are modafinil and armodafinil, which are cognitive-enhancing and weight-promoting agents. They are atypical stimulants FDA approved for narcolepsy, shift work sleep disorder, and adjunctive treatment for obstructive sleep apnea. Interestingly, significant improvement with these agents has been seen for children with ADHD in home and school settings but not adults. Modafinil did not separate from placebo. So, it could be reasonably considered for pediatric ADHD patients who do not respond or cannot tolerate FDA-approved ADHD treatments. Furthermore, armodafinil may have a better effect on alertness and arousal throughout the day than modafinil. It is experimental and not FDA approved but potentially another option to consider.

So, the take-home point is that there are excellent nonstimulant options, which may be especially effective for certain populations of ADHD. Atomoxetine, for example, may be especially good for ADHD with comorbid anxiety; viloxazine for ADHD with comorbid depression; bupropion, an exciting option for patients with smoking cessation; and alpha-2 extended-release agents for patients with hyperarousal, aggression, tics, insomnia, and when adjunct treatment is needed with stimulants.

Abstract

Nonstimulant Treatments for ADHD

Jeffrey H Newcorn, Beth Krone, Ralf W Dittmann

Nonstimulants have an important role when response or tolerability to psychostimulants is poor, when certain comorbid disorders are present, or if patients prefer nonstimulants. Here, we discuss monotherapy and combined treatment of ADHD and review mechanism of action, pharmacokinetics, efficacy, tolerability, and safety of approved, off-label, and pipeline nonstimulants. We present detailed information regarding the 4 FDA-approved nonstimulant medications-the norepinephrine reuptake inhibitors, atomoxetine and viloxazine extended release, and the α-2 adrenergic agonists, clonidine XR and guanfacine XR. We additionally review evidence regarding the off-label use of a variety of other medications. Variability across and within drug classes in nature of response, approach to titration, and temporal characteristics of treatment allow a nuanced treatment approach for individuals with comorbid disorders and complicated clinical presentations. Availability of nonstimulant medications enhances our opportunity to offer personalized treatment of ADHD across the lifespan.

Reference

Newcorn, J. H., Krone, B., & Dittmann, R. W. (2022). Nonstimulant treatments for ADHD. Child and Adolescent Psychiatric Clinics of North America, 31(3), 417-435.