TCPR: What is the advantage of nonstimulants in ADHD?

Dr. Nissen: One advantage is safety. Stimulants have an abuse potential, particularly the amphetamines and the short-acting versions, which can be crushed or snorted. Diversion is pretty common—8.5% of college students use nonprescribed stimulant medications. Then there are cardiovascular risks, which are worse with long-term use. The risk of heart disease—mainly hypertension and arterial disease—increased steadily by 4% per year in children and adults, according to a recent large case-controlled study (Zhang L et al, JAMA Psychiatry 2024;81(2):178–187).

TCPR: But aren’t stimulants more effective?

Dr. Nissen: Yes, but not by as much as people think. Here’s how their effect sizes compare:

• Stimulants: 0.8–0.9
• Clonidine (Kapvay): 0.7–0.8
• Guanfacine (Intuniv): 0.4–0.9
• Viloxazine (Qelbree): 0.5–0.6
• Atomoxetine (Strattera): 0.4–0.6
• Bupropion (off-label): 0.3–0.5

To put that in perspective, the average effect size for psychiatric treatments is 0.5. So while the stimulants are clearly at the top, the nonstimulants still have a respectable effect. One limitation here is that most of those figures come from trials in children and adolescents (Childress A, Expert Opin Pharmacother 2024;25(7):853–866).

TCPR: Do the nonstimulants work in adults and children?

Dr. Nissen: Atomoxetine and viloxazine are approved in both age groups, but the alpha-2 agonists, clonidine and guanfacine, are only approved in children. Of those two, guanfacine is the only one with trials in adult ADHD (Ota T et al, Drug Des Devel Ther 2021;15:1965–1969). Bupropion is off-label in ADHD, and it has trials in children and adults.

TCPR: So their benefits are a little lower. Do they affect different symptoms?

Dr. Nissen: In terms of ADHD subtypes, the inattentive type is more common in adults, but no medication stands out as more effective for particular subtypes. One difference is that stimulants are going to make people feel more energized. The nonstimulants are not going to do that, and the alpha-2 agonists, particularly clonidine, can cause sedation. On the other hand, the alpha-2 agonists can improve sleep, and that’s where the nonstimulants have an edge: in treating comorbidities. 

TCPR: How so?

Dr. Nissen: I’d consider viloxazine and bupropion for ADHD with depression, and bupropion for nicotine cessation. Atomoxetine and viloxazine are both repurposed antidepressants. They are norepinephrine reuptake inhibitors, with additional serotonin activity for viloxazine. Viloxazine is approved for depression outside the US, where it’s been used since the 1970s. Atomoxetine doesn’t have approval for depression anywhere because it failed in those trials, but it does help ­anxiety disorders that are comorbid with ADHD in adults and children—social and generalized anxiety (Khoodoruth MAS et al, Res Dev Disabil 2022;128:104275).

TCPR: What about clonidine and guanfacine?

Dr. Nissen: I’d consider those for anxiety as well, particularly clonidine. It has small studies in PTSD and panic disorder, and it may help nightmares, but these studies are very preliminary. A related alpha-2 agonist, dexmedetomidine, is currently being explored by the industry for posttraumatic stress disorder. Clonidine also improved mania in small trials (Ahmadpanah M et al, J Psychiatr Res 2022;146:163–171). Both of the alpha-2 agonists are effective for tics, which are a rare side effect of stimulants. In my own practice, I go with guanfacine more because it has better evidence in adults. It is also less sedating, and I see fewer complaints of “brain fog.”

TCPR: When do you give up on nonstimulants? 

Dr. Nissen: After one or two failures, I’ll usually go with a stimulant, in which case my go-to is a methylphenidate product, usually an extended-release (ER) formulation like methylphenidate ER (Concerta). However, if the patient has a history of substance use disorder, I’m likely to stick with the nonstimulant category.

TCPR: What formulations of guanfacine and clonidine do you use? 

Dr. Nissen: I tend to use the ER versions. Those are the ones that are FDA approved, but some of the earlier studies used immediate release, so that is feasible. I usually dose it all at night to prevent sedation during the day. I’ll start with the lowest dose and raise it every week based on tolerability and efficacy (see the table “Nonstimulants in ADHD”). 

TCPR: When a patient is already taking an antihypertensive, how do you work with clonidine and guanfacine?

Dr. Nissen: Certainly it’s a good idea to check blood pressure before starting and to monitor it closely. I also check if they’ve had any history of hypotension, falls, or syncope and might avoid these medications if so. I’ll coordinate with their primary care physician, but most patients can remain on their blood pressure regimen while starting these alpha-2 agonists. Also exercise caution with mirtazapine, which has the opposite action at the alpha-2 receptor. There are a few case reports of hypertensive urgency when mirtazapine is combined with an alpha-2 agonist (Abo-Zena RA et al, Pharmacotherapy 2000;20(4):476–478).

TCPR: What are the risks with atomoxetine and viloxazine?

Dr. Nissen: The most common risks are GI side effects, which improve by taking them with food. These medications can be sedating, but they can also cause insomnia. Atomoxetine can be given once or twice a day; its half-life is five hours. Viloxazine has a shorter half-life (two to five hours) but is still given once a day as it comes as ER capsules that can also be opened and sprinkled. Both can raise blood pressure and heart rate. Atomoxetine has additional warnings about rare sudden cardiac death from arrhythmias, similar to the warnings on stimulants. Viloxazine isn’t known to cause that and doesn’t have that warning. Generally, atomoxetine is well tolerated, but around one in 10 patients can have problems with it because they are poor metabolizers at CYP2D6, which raises the blood levels by as much as 16-fold (Childress A, Expert Opin Pharmacother 2024;25(7):853–866).

TCPR: How long do atomoxetine and viloxazine take to work?

Dr. Nissen: I’d suggest a trial of four to six weeks before making a change; same timeline with bupropion. 

TCPR: What about the modafinils (modafinil/Provigil; armodafinil/Nuvigil)?

Dr. Nissen: Modafinil is not FDA approved for ADHD. It does have support from randomized controlled trials, but I don’t use it often. I know other people do, but as far as I’m concerned, at that point you might as well be considering a stimulant. So for me, I might try a modafinil if both the stimulants and nonstimulants have failed.

TCPR: How do you separate valid ADHD from other cognitive problems?

Dr. Nissen: First, rule out other psychiatric disorders that could be causing the problem, especially mood and anxiety disorders. Next, focus on childhood history. You need that to diagnose ADHD (onset before age 12), so ask about school performance and whether the patient required any neuropsych evaluations or accommodations as they were growing up. Finally, conduct a structured interview to assess all the symptoms, and look for real-life examples of those symptoms. In the end, ADHD is a clinical diagnosis, which means you don’t need a neuropsych evaluation or a computerized battery like the QbTest to diagnose it. Those tools can help provide clarity when the diagnosis is unclear, though. 

TCPR: Are any supplements useful for ADHD?

Dr. Nissen: They are promising, but here the evidence is much weaker. Those that have at least small controlled trials include phosphatidylserine, fish oil, ginkgo biloba, ginseng, and probiotics. One I find interesting is phosphatidylserine.

TCPR: That’s a phospholipid, right?

Dr. Nissen: Yes. Phosphatidylserine is a naturally occurring membrane phospholipid that is thought to change neurotransmitter signaling by altering receptors, enzymes, and ion channels. We get phosphatidylserine from foods like egg yolks and soybeans, and taking more than what’s in the usual diet led to improvements in children with ADHD in a small randomized trial (n=37, 200–300 mg/day) as well as in a few other trials where it was combined with omega-3 fatty acids, another membrane phospholipid with support in ADHD (Hirayama S et al, J Hum Nutr Diet 2014;27 Suppl 2:284–291). This phosphatidylserine + omega-3 combo used to be sold as a prescription supplement for ADHD, Vayarin. I’d take this efficacy research with a grain of salt, but it is safe and well tolerated, although like omega-3 it does have a blood-thinning effect. Consumer Labs tested phosphatidylserine products and found good results with Puritan’s Pride, Life Extension, GNC, Jarrow, Swanson, and Doctor’s Best (Now and Nutricost did not pass). 

TCPR: Which other supplements have you found useful?

Dr. Nissen: Ginkgo biloba (80–120 mg/day) has a small controlled trial where it augmented methylphenidate in children and adolescents with ADHD (Shakibaei F et al, Complement Ther Clin Pract 2015;21(2):61–67). Another supplement to know about is nicotine—clearly not recommended, but people with ADHD have higher rates of nicotine use, and some of this may be to treat symptoms. Nicotine patches and nicotine agonists improve ADHD symptoms. If patients are smoking, I’ll recommend that they switch to a nicotine gum and/or patch.

TCPR: What lifestyle approaches do you recommend for ADHD?

Dr. Nissen: Exercise is top on my list. I recommend aerobic exercise 30 minutes a day at least three days a week, preferably five. There are studies showing benefits on cognitive tests, and physiologically it improves circulation, oxygenation, and neuroprotection through brain-derived neurotrophic factor production. Clinically, I often see ADHD worsen when young adults drop their high school sports teams as they transition to college.

TCPR: What else is high on your list?

Dr. Nissen: Substance use is a low-hanging fruit, in particular cannabis. In online forums, many lay people discuss cannabis as if it were effective self-medication for ADHD (Mitchell JT et al, PLoS One 2016;11(5):e0156614). That’s the perception, but in the studies cannabis impairs verbal learning, memory, and attention, especially in people under age 25 (Broyd SM, Biol Psychiatry 2016;79(7):557–567). GABAergic substances like alcohol and benzos can also impair attention and focus, and with alcohol we need to look at next-day effects from sleep disruption and hangover. 

TCPR: How important is sleep for ADHD?

Dr. Nissen: That’s also top on my list. Sleep deprivation will worsen most cognitive symptoms, including impulsivity. I ask not just if they have trouble falling asleep but also about their sleep quality, nocturnal awakening, and signs of sleep apnea like loud snoring or waking up short of breath. For people with ADHD who are also night owls, addressing their sleep schedule with chronotherapeutics can help. In one controlled trial of 51 adults with ADHD with a delay in sleep onset, melatonin 0.5 mg at night helped them fall asleep earlier and improved their ADHD symptoms a little (van Andel E et al, Chronobiol Int 2021;38(2):260–269).

TCPR: What about psychotherapy for ADHD?

Dr. Nissen: Definitely. There are three approaches I recommend: cognitive behavioral therapy (CBT), cognitive remediation, and coaching. There is a new form of CBT for ADHD that combines emotional skills and executive functioning skills like managing calendars and task lists, removing distractions, prioritization, and organization. There’s a great Treatments That Work manual called Mastering Your Adult ADHD that has a workbook for the patient (Safren SA et al, Oxford University Press; 2017). Cognitive remediation (also called cognitive training) is typically done by neuropsychologists. It includes the skills from CBT and adds memory training games, often computerized, to improve specific deficits. Finally, lay persons often offer coaching. Executive functioning coaches help build planning, organization, and time management skills. Coaching can be very helpful, but is usually not covered by insurance.

TCPR: Thank you for your time, Dr. Nissen.